KR20100135325A - Modulators of dopamine neurotransmission - Google Patents

Abstract

The present invention relates to novel 1- (2,3-dihydro-1,4-benzodioxin-2-yl) -methanamine derivatives useful as modulators of dopamine neurotransmission, and more particularly as dopamine stabilizers. will be. In another aspect, the invention relates to the use of these compounds in a method of treatment and to pharmaceutical compositions comprising the compounds of the invention.

Description

Modulators of dopamine neurotransmission

The present invention relates to 1- (2,3-dihydro-1,4-benzodioxin-2-yl) -methanamine derivatives useful as modulators of dopamine neurotransmission, and more particularly as dopamine stabilizers.

In another aspect, the invention relates to the use of these compounds in a method of treatment and to pharmaceutical compositions comprising the compounds of the invention.

Dopamine is a neurotransmitter in the brain. Since this discovery was made in the 1950s, the function of dopamine in the brain has been intensively studied. To date, dopamine has been established to be important in some aspects of brain function, including exercise, cognition, sensation, emotion and autonomic functions (eg, regulation of appetite, body temperature, sleep). Thus, modulation of dopaminergic function can be beneficial in the treatment of a wide range of disorders affecting brain function. In fact, drugs that act directly or indirectly at central dopamine receptors are commonly used in the treatment of neurological and mental diseases such as Parkinson's disease and schizophrenia. However, currently available dopaminergic agents can have serious side effects. One class of compounds that act through the dopamine system of the brain is dopamine stabilizers, which have been found to be useful in the treatment of both neurological and mental disorders.

Typical pharmacological effects characteristic of dopaminergic stabilizers include: 1) increased conduction of dopamine in the distal portion of the ascending dopaminertic process of the mammalian brain; 2) absent or mild behavioral effects in other untreated rats; And 3) inhibition of behavioral effects induced by neurostimulatory or psychotic compounds in rats. In the present invention they are referred to as dopaminergic stabilizer profiles.

State of the art

WO 2005/105776 discloses arylsulfonyl benzodioxanes useful as modulators of 5-HT6 and 5-HT2A receptors.

WO 2006/116158 discloses benzodioxane and benzodioxolane derivatives useful as partial agonists or agonists at the 5-HT2C receptor.

See Avner et al. in Journal of Medicinal Chemistry 1974 17 (2) 197-200 discloses substituted 1,4-benzodioxanes as reversible and irreversible antagonists at adrenergic receptors.

Various chlorinated 1,4-benzodioxanes are disclosed as ligands for α1 and α2-receptors. Pharmacology 1983 26 (5) 258-69; Molecular Pharmacology 1981 20 (2) 295-301; Croatica Chemica Acta 1957 29 363-367; and Gazzetta Chimica ltaliana 1957 87 1303-1305.

Compound 3-morpholin-4-ylmethyl-2,3-dihydro-benzo [1,4] dioxin-6-carbonitrile is described in Funke et al .; Synthesis of 7-substituted-2-aminomethyl-1,4-benazodioxanes; Gazzetta Chimica ltaliana 1961 91 1268-1281 are disclosed as synthetic intermediates.

Finally, US Pat. No. 5,126,366 describes certain aminophenoxyalkyl derivatives of benzodioxane, and US Pat. Nos. 5,166,367 and US 5,189,171 describe certain antipsychotic benzodioxane derivatives; US Pat. No. 5,235,055 describes certain antipsychotic quinoline derivatives of benzodioxane methylamine, US Pat. No. 5,245,051 describes certain antipsychotic chroman derivatives of benzodioxane methylamine, US Pat. No. 5,318,988 The arc describes only specific 2-aminomethyl-chrom.

However, no 1- (2,3-dihydro-1,4-benzodioxin-2-yl) methanamine derivatives of the present invention and their use as dopaminergic stabilizers have been reported.

Summary of the Invention

It is an object of the present invention to provide novel pharmaceutically active compounds which are particularly useful for the treatment of disorders in the central nervous system. Another object of the present invention is to provide a compound for regulating the dopaminergic system in mammalian brain, including the human brain. It is another object of the present invention to provide novel compounds having a dopaminergic stabilizer profile. It is a further object of the present invention to provide compounds having a therapeutic effect after oral administration. It is a further object of the present invention to provide compounds having more optimal pharmacodynamic properties such as motor behavior, bioavailability, solubility and efficacy. It is a further object of the present invention to provide compounds which are superior to currently known dopaminergic compounds in terms of efficacy and side effects in the treatment of several disorders associated with dysfunction of the CNS.

The present invention relates to the unexpected discovery of the pharmacological effect of the compound of formula 1 on the dopaminergic system in the brain. In vivo pharmacological tests in rats have demonstrated that the compounds of the present invention have effects on the biochemical indicators of the brain with the inherent characteristics of dopamine antagonists.

In a first aspect, the present invention provides a compound of Formula 1, any of its stereoisomers, or any mixture of stereoisomers thereof, or N-oxides or pharmaceutically acceptable salts thereof.

In Chemical Formula 1,

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and X are as defined below.

In a second aspect, the invention provides a compound of the invention, any of its stereoisomers, or any mixture of stereoisomers thereof, or N-oxides thereof, in combination with one or more pharmaceutically acceptable carriers, excipients or diluents Or a pharmaceutically acceptable salt thereof in a therapeutically effective amount.

In a further aspect, the present invention provides a compound of the present invention for preparing a pharmaceutical composition for the treatment, prevention or alleviation of a disease, disorder or condition in response to the modulation of dopaminergic function in the central nervous system of a mammal, including human, The use of any of its stereoisomers, or all mixtures of stereoisomers thereof, or their N-oxides or pharmaceutically acceptable salts thereof.

In a further aspect, the invention provides a therapeutically effective amount of a compound of the invention, any of its stereoisomers, or any mixture of stereoisomers thereof, or N-oxides or pharmaceutically acceptable salts thereof thereof. To a method of treating, preventing or alleviating a disease, disorder or condition in response to the regulation of dopaminergic function in the central nervous system of the body of a living animal, including a human, comprising administering to the body of a living animal in need thereof. will be.

Other aspects of the invention will be apparent to those of ordinary skill in the art from the following detailed description and examples.

1- (2,3-dihydro-1,4-benzodioxin-2-yl) methanamine derivative

In a first aspect, the present invention provides a compound of Formula 1, any of its stereoisomers, or any mixture of stereoisomers thereof, or N-oxides or pharmaceutically acceptable salts thereof.

Formula 1

In Chemical Formula 1,

X is O, S, NH or CH ₂ ;

R ¹ is selected from the group consisting of SOR ⁸ , SO ₂ R ⁸ , SO ₂ NH ₂ , SO ₂ NHCH ₃ and SO ₂ N (CH ₃ );

R ² is selected from the group consisting of H, CN, F, Cl, Br, I and CH ₃ ;

및

로 이루어진 그룹으로부터 선택되고; R ³ is C ₁ -C ₅ alkyl, allyl, CH ₂ CH ₂ OCH ₃ , CH ₂ CH ₂ CH ₂ F, CH ₂ CH ₂ CHF ₂ , CH ₂ CH ₂ F, 3,3,3-trifluoropropyl , 4,4,4-trifluorobutyl, CH ₂ CH ₂ OH, CH ₂ CH ₂ CH ₂ OH, CH ₂ CH (OH) CH ₃ , CH ₂ CH ₂ COCH ₃ , C ₃ -C ₆ cycloalkyl,

And

Is selected from the group consisting of;

및

로 이루어진 그룹으로부터 선택되거나;R ⁴ is H, C ₁ -C ₅ alkyl, allyl, CH ₂ CH ₂ OCH ₃ , CH ₂ CH ₂ CH ₂ F, CH ₂ CH ₂ CHF ₂ , CH ₂ CH ₂ F, 3,3,3-trifluoro Ropropyl, 4,4,4-trifluorobutyl, CH ₂ CH ₂ OH, CH ₂ CH ₂ CH ₂ OH, CH ₂ CH (OH) CH ₃ , CH ₂ CH ₂ COCH ₃ ,

And

Selected from the group consisting of;

R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 4 to 6 membered heterocyclic ring, wherein the heterocyclic ring is one oxygen atom and / or one additional nitrogen atom as ring member May optionally include; The heterocyclic ring may be optionally substituted with C ₁ -C ₅ alkyl;

R ⁵ , R ⁶ and R ⁷ are selected from the group consisting of H and CH ₃ ;

R ⁸ is selected from the group consisting of C ₁ -C ₃ alkyl, CF ₃ , CHF ₂ , CH ₂ F and CN.

In a more preferred embodiment, the compound of the present invention is a compound of formula 1A, any of its stereoisomers, or all mixtures of stereoisomers thereof, or N-oxides or pharmaceutically acceptable salts thereof.

Formula 1A

In Chemical Formula 1A,

X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above.

In a more preferred embodiment, the compound of the invention is a compound of formula 1B, any of its stereoisomers, or all mixtures of stereoisomers thereof, or N-oxides or pharmaceutically acceptable salts thereof.

Formula 1B

In Chemical Formula 1B,

X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above.

In a more preferred embodiment, the compounds of the present invention are compounds of formula 1, 1A or 1B, any of stereoisomers thereof, or any mixture of stereoisomers thereof, wherein X is O, S, NH or CH ₂ . N-oxides or pharmaceutically acceptable salts thereof.

In a more preferred embodiment, X is O.

In another preferred embodiment, X is S.

In a more preferred third embodiment, X is NH.

In a more preferred fourth embodiment, X is CH ₂ .

In another preferred embodiment, the compound of the present invention is

R ¹ is selected from the group consisting of SOR ⁸ , SO ₂ R ⁸ , SO ₂ NH ₂ , SO ₂ NHCH ₃ and SO ₂ N (CH ₃ );

Of the compound of Formula 1, 1A or 1B, any of its stereoisomers, or stereoisomers thereof, wherein R ⁸ is selected from the group consisting of C ₁ -C ₃ alkyl, CF ₃ , CHF ₂ , CH ₂ F and CN All mixtures, or N-oxides thereof or pharmaceutically acceptable salts thereof.

In a more preferred embodiment, R ¹ is SOR ⁸ and R ⁸ is selected from the group consisting of C ₁ -C ₃ alkyl, CF ₃ , CHF ₂ , CH ₂ F and CN.

In another more preferred aspect, R ¹ is SO ₂ R ⁸ and R ⁸ is selected from the group consisting of C ₁ -C ₃ alkyl, CF ₃ , CHF ₂ , CH ₂ F and CN.

In a more preferred third embodiment, R ¹ is SO ₂ R ⁸ and R ⁸ is selected from the group consisting of C ₁ -C ₃ alkyl and CF ₃ .

In a more preferred fourth embodiment, R ¹ is SO ₂ NH ₂ .

In a more preferred fifth embodiment, R ¹ is SO ₂ NHCH ₃ .

In a more preferred sixth embodiment, R ¹ is SO ₂ N (CH ₃ ).

In a more preferred seventh aspect, R ¹ is selected from the group consisting of SO ₂ CH ₃ and SO ₂ CF ₃ .

In a third preferred embodiment, the compound of the present invention is

A compound of Formula 1, 1A or 1B, any of its stereoisomers, or any mixture of stereoisomers thereof, wherein R ² is selected from the group consisting of H, CN, F, Cl, Br, I and CH ₃ ; or N-oxides or pharmaceutically acceptable salts thereof.

In a more preferred embodiment, R ² is H.

In another more preferred aspect, R ² is CN.

In a more preferred third embodiment, R ² is F.

In a more preferred fourth embodiment, R ² is Cl.

In a more preferred fifth embodiment, R ² is Br.

In a more preferred sixth embodiment, R ² is I.

In a more preferred seventh aspect, R ² is CH ₃ .

In a more preferred eighth aspect, R ² is selected from the group consisting of H, F and Cl.

In a fourth preferred embodiment, the compound of the invention is

및

로 이루어진 그룹으로부터 선택되는, 화학식 1, 1A 또는 1B의 화합물, 이의 입체이성체들 중의 어느 것, 또는 이의 입체이성체들의 모든 혼합물, 또는 이들의 N-옥사이드 또는 약제학적으로 허용되는 이들의 염이다.R ³ is C ₁ -C ₅ alkyl, allyl, CH ₂ CH ₂ OCH ₃ , CH ₂ CH ₂ CH ₂ F, CH ₂ CH ₂ CHF ₂ , CH ₂ CH ₂ F, 3,3,3-trifluoropropyl , 4,4,4-trifluorobutyl, CH ₂ CH ₂ OH, CH ₂ CH ₂ CH ₂ OH, CH ₂ CH (OH) CH ₃ , CH ₂ CH ₂ COCH ₃ , C ₃ -C ₆ cycloalkyl,

And

A compound of Formula 1, 1A or 1B, any of its stereoisomers, or any mixture of stereoisomers thereof, or N-oxides or pharmaceutically acceptable salts thereof, selected from the group consisting of:

In a more preferred embodiment, R ³ is C ₁ -C ₅ alkyl.

In another more preferred aspect, R ³ is allyl.

In a more preferred third embodiment, R ³ is CH ₂ CH ₂ OCH ₃ .

In a more preferred fourth embodiment, R ³ is CH ₂ CH ₂ CH ₂ F.

In a more preferred fifth embodiment, R ³ is CH ₂ CH ₂ CHF ₂ .

In a more preferred sixth embodiment, R ³ is CH ₂ CH ₂ F.

In a more preferred seventh aspect, R ³ is 3,3,3-trifluoropropyl.

In a more preferred eighth aspect, R ³ is 4,4,4-trifluorobutyl.

In a more preferred ninth embodiment, R ³ is CH ₂ CH ₂ OH.

In a more preferred tenth aspect, R ³ is CH ₂ CH ₂ CH ₂ OH.

In a more preferred eleventh aspect, R ³ is CH ₂ CH (OH) CH ₃ .

In a more preferred twelfth embodiment, R ³ is CH ₂ CH ₂ COCH ₃ .

In a more preferred thirteenth embodiment, R ³ is C ₃ -C ₆ cycloalkyl.

이다.In a more preferred fourteenth aspect, R ³ is

to be.

이다.In a more preferred fifteenth aspect, R ³ is

to be.

In a more preferred sixteenth aspect, R ³ is selected from the group consisting of C ₁ -C ₅ alkyl, allyl, 3,3,3-trifluoropropyl, CH ₂ CH ₂ OCH ₃ and CH ₂ CH ₂ OH.

In a fifth preferred embodiment, the compound of the present invention is

및

로 이루어진 그룹으로부터 선택되는, 화학식 1, 1A 또는 1B의 화합물, 이의 입체이성체들 중의 어느 것, 또는 이의 입체이성체들의 모든 혼합물, 또는 이들의 N-옥사이드 또는 약제학적으로 허용되는 이들의 염이다.R ⁴ is H, C ₁ -C ₅ alkyl, allyl, CH ₂ CH ₂ OCH ₃ , CH ₂ CH ₂ CH ₂ F, CH ₂ CH ₂ CHF ₂ , CH ₂ CH ₂ F, 3,3,3-trifluoro Ropropyl, 4,4,4-trifluorobutyl, CH ₂ CH ₂ OH, CH ₂ CH ₂ CH ₂ OH, CH ₂ CH (OH) CH ₃ , CH ₂ CH ₂ COCH ₃ ,

And

A compound of Formula 1, 1A or 1B, any of its stereoisomers, or any mixture of stereoisomers thereof, or N-oxides or pharmaceutically acceptable salts thereof, selected from the group consisting of:

In a more preferred embodiment, R ⁴ is H.

In another more preferred aspect, R ⁴ is C ₁ -C ₅ alkyl.

In a more preferred third embodiment, R ⁴ is allyl.

In a fourth more preferred embodiment, R ⁴ is CH ₂ CH ₂ OCH ₃ .

In a more preferred fifth embodiment, R ⁴ is CH ₂ CH ₂ CH ₂ F.

In a more preferred sixth embodiment, R ⁴ is CH ₂ CH ₂ CHF ₂ .

In a more preferred seventh aspect, R ⁴ is CH ₂ CH ₂ F.

In a more preferred eighth aspect, R ⁴ is 3,3,3-trifluoropropyl.

In a more preferred ninth embodiment, R ⁴ is 4,4,4-trifluorobutyl.

In a more preferred tenth aspect, R ⁴ is CH ₂ CH ₂ OH.

In a more preferred eleventh aspect, R ⁴ is CH ₂ CH ₂ CH ₂ OH.

In a more preferred twelfth embodiment, R ⁴ is CH ₂ CH (OH) CH ₃ .

In a more preferred thirteenth embodiment, R ⁴ is CH ₂ CH ₂ COCH ₃ .

이다.In a more preferred fourteenth aspect, R ⁴ is

to be.

이다.In a more preferred fifteenth aspect, R ⁴ is

to be.

In a more preferred sixteenth aspect, R ⁴ is selected from the group consisting of H and C ₁ -C ₅ alkyl.

In a sixth preferred embodiment, the compound of the present invention

R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring, wherein the heterocyclic ring is one oxygen atom and / or one additional nitrogen atom as ring member Optionally includes; The heterocyclic ring may be optionally substituted with C ₁ -C ₅ alkyl, a compound of Formula 1, 1A or 1B, any of its stereoisomers, or all mixtures of stereoisomers thereof, or N-oxides thereof or Pharmaceutically acceptable salts thereof.

In a more preferred embodiment, R ³ and R ⁴ together with the nitrogen atom to which they are attached form a four membered heterocyclic ring, wherein said heterocyclic ring may be optionally substituted with C ₁ -C ₅ alkyl.

In another more preferred aspect, R ³ and R ⁴ together with the nitrogen atom to which they are attached form a five membered heterocyclic ring, wherein said heterocyclic ring may be optionally substituted with C ₁ -C ₅ alkyl have.

In a more preferred third embodiment, R ³ and R ⁴ together with the nitrogen atom to which they are attached form a six membered heterocyclic ring, wherein said heterocyclic ring is one oxygen atom and / or one as ring member Optionally further nitrogen atoms of; The heterocyclic ring may be optionally substituted with C ₁ -C ₅ alkyl.

In a more preferred fourth embodiment, R ³ and R ⁴ together with the nitrogen atom to which they are attached form a six membered heterocyclic ring, wherein said heterocyclic ring may optionally comprise one oxygen atom as ring member Can; The heterocyclic ring may be optionally substituted with C ₁ -C ₅ alkyl.

In a more preferred fifth embodiment, R ³ and R ⁴ together with the nitrogen atom to which they are attached form a six membered heterocyclic ring, wherein said heterocyclic ring may be optionally substituted with C ₁ -C ₅ alkyl have.

In a more preferred sixth embodiment, R ³ and R ⁴ together with the nitrogen atom to which they are attached form a six membered heterocyclic ring, wherein said heterocyclic ring may optionally comprise one oxygen atom as ring member Can be.

In a more preferred seventh aspect, R ³ and R ⁴ together with the nitrogen atom to which they are attached form acetidine, pyrrolidine, piperidine, C ₁ -C ₅ alkyl-piperidine or morpholine .

In a more preferred eighth aspect, R ³ and R ⁴ together with the nitrogen atom to which they are attached form an acetidine group.

In a more preferred ninth embodiment, R ³ and R ⁴ together with the nitrogen atom to which they are attached form a pyrrolidine group.

In a more preferred tenth aspect, R ³ and R ⁴ together with the nitrogen atom to which they are attached form a piperidine group.

In a more preferred eleventh aspect, R ³ and R ⁴ together with the nitrogen atom to which they are attached form a C ₁ -C ₅ alkyl-piperidine group.

In a more preferred twelfth embodiment, R ³ and R ⁴ together with the nitrogen atom to which they are attached form a morpholine group.

In a seventh preferred embodiment, the compound of the present invention is

A compound of Formula 1, 1A or 1B, any of stereoisomers thereof, or any mixture of stereoisomers thereof, or N-, wherein R ⁵ , R ⁶ and R ⁷ are selected from the group consisting of H and CH _3; Oxides or pharmaceutically acceptable salts thereof.

In a more preferred embodiment, R ⁵ , R ⁶ and R ⁷ are each H.

In an eighth preferred embodiment, the compound of the present invention is

X is O or CH ₂ ;

R ¹ is SO ₂ R ⁸ ;

R ² is H, F or Cl;

R ³ is C ₁ -C ₅ alkyl, allyl, CH ₂ CH ₂ OCH ₃ , 3,3,3-trifluoropropyl or CH ₂ CH ₂ OH;

R ⁴ is H or C ₁ -C ₅ alkyl;

R ³ and R ⁴ together with the nitrogen atom to which they are attached form an acetidine, pyrrolidine, piperidine, C ₁ -C ₅ alkyl-piperidine or morpholine group;

R ⁵ , R ⁶ and R ⁷ are all H;

A compound of Formula 1, 1A or 1B, any of its stereoisomers, or any mixture of stereoisomers thereof, or N-oxides or pharmaceutically acceptable thereof, wherein R ⁸ is C ₁ -C ₃ alkyl or CF ₃ Salts thereof.

In a further preferred embodiment, the compounds of the present invention

N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -propan-1-amine;

N-{[(2R) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -propan-1-amine;

N-{[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -propan-1-amine;

N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;

N-{[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;

1-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} piperidine;

1-{[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} piperidine;

1-{[(2R) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} piperidine;

N-methyl-1- [7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxyn-2-yl] methanamine;

N-methyl-1-[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxyn-2-yl] methanamine;

1-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} pyrrolidine;

3-methyl-1-{[(2R) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} piperidine;

2-methyl-N-{[(2R) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine;

2-methyl-N-{[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine;

N-methyl-N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine;

N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-propylpropan-1-amine;

N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-propan-1-amine;

N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;

N-{[(2S) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;

1- [5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] -N-methylmethanamine;

N-{[(2S) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine;

N-{[(2S) -7- (trifluoromethylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;

N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} -N-propan-1-amine;

N-{[(2S) -7- (trifluoromethylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine;

N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} prop-2-en-1-amine;

4-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} morpholine;

N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} butan-1-amine;

N, N-dimethyl-N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methanamine;

N-ethyl-N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;

N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-2-amine;

N-ethyl-N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-propan-1-amine;

2-({[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} amino) ethanol;

N-methyl-N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;

2-methoxy-N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;

1-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} azetidine;

2-methyl-N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine;

N-{[(2S) -8-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;

N-{[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N- (3,3,3-trifluoro Propyl) amine;

N-{[(2S) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N- (3,3, 3-trifluoropropyl) amine;

1-[(2S) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] -N-methylmethanamine;

N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} prop-2-en-1-amine;

4-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} morpholine;

N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} butan-1-amine;

N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-propylpropan-1-amine;

1- [5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] -N, N-dimethylmethanamine;

N-ethyl-N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;

N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-2-amine;

N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-methylpropan-1-amine;

N-ethyl-N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine;

2-({[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} amino) ethanol;

N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-methylethanamine;

N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -2-methoxyethanamine;

1-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} azetidine;

N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -2-methylpropan-1-amine;

1-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} pyrrolidine;

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} prop-2-ene-1- Amines;

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} butan-1-amine;

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-propylpropan-1-amine ;

1-[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] -N, N-dimethylmethanamine;

N-ethyl-N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-2-amine;

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-methylpropan-1-amine ;

N-ethyl-N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine ;

2-({[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} amino) ethanol;

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-methylethanamine;

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -2-methoxyethanamine;

1-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} azetidine;

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -2-methylpropan-1-amine ;

1-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} pyrrolidine;

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -propan-1-amine;

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -3-fluoropropane-1- Amines;

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -2,2-dimethylpropane-1 Amines;

1-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} piperidine;

1-[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] -N-methylmethanamine;

N-{[(2S) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -propan-1-amine;

2,2-dimethyl-N-{[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine;

N-methyl-1- [7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methanamine;

N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} ethanamine;

N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} prop-2-en-1-amine;

4-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} morpholine;

N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} butan-1-amine;

N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} -N-propylpropan-1-amine;

N, N-dimethyl-1- [7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methanamine;

N-ethyl-N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} ethanamine;

N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} propan-2-amine;

N-methyl-N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} propan-1-amine;

N-ethyl-N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} propan-1-amine;

2-({[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} amino) ethanol;

N-methyl-N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} ethanamine;

2-methoxy-N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} ethanamine;

1-{[7- (methylsulfonyl) -3,4-dihydro-2H-croken-2-yl] methyl} azetidine;

2-methyl-N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} propan-1-amine;

1-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} pyrrolidine;

1-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} piperidine;

3-fluoro-N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} propan-1-amine;

4-{[(S) -5-Fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} morpholine; or

N-({(2S) -7-[(trifluoromethyl) sulfonyl] -2,3-dihydro-1,4-benzodioxin-2-yl} methyl) propan-2-amine, its steric Any of the isomers, or all mixtures of stereoisomers thereof, or their N-oxides or pharmaceutically acceptable salts thereof.

In a further preferred embodiment, the compound of the invention is N-{[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl}- Propan-1-amine; Any of its stereoisomers, or all mixtures of stereoisomers thereof, or N-oxides or pharmaceutically acceptable salts thereof.

In a more preferred third embodiment, the compound of the invention is N-{[(2S) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2 General] methyl} ethanamine; Any of its stereoisomers, or all mixtures of stereoisomers thereof, or N-oxides or pharmaceutically acceptable salts thereof.

In a more preferred fourth embodiment, the compound of the invention is N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl ] Methyl} ethanamine; Any of its stereoisomers, or all mixtures of stereoisomers thereof, or N-oxides or pharmaceutically acceptable salts thereof.

Any combination of two or more of the above described embodiments is considered to be within the scope of the present invention.

Definition of Substituents

In the context of the present invention, C ₁ -C ₅ alkyl means a straight or branched chain of 1 to 5 carbon atoms, including but not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, i -Butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neo-pentyl.

C ₃ -C ₆ cycloalkyl refers to a cyclic alkyl group containing 3 to 6 carbon atoms and includes cyclopropyl, cyclobutyl and cyclopentyl.

The term "allyl" refers to the group -CH ₂ -CH = CH ₂ .

4- to 6-membered heterocyclic rings comprising at least one nitrogen atom include, for example, but not limited to, acetidine, pyrrolidine, piperidine and morpholine.

Pharmaceutically acceptable salts

The chemical compounds of the present invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (ie physiologically) acceptable salts of the chemical compounds of the present invention, and predrug or prodrug forms.

Examples of pharmaceutically acceptable addition salts include, but are not limited to, nontoxic inorganic and organic acid addition salts such as hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconate, ascorbate, Benzenesulfonate, benzoate, cinnamate, citrate, emborate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, Phthalates, salicylates, sorbates, stearates, succinates, tartrates and toluene-p-sulfonates, and the like). Such salts may be formed by methods known and described in the art.

Other acids, such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates to obtain the chemical compounds of the invention and their pharmaceutically acceptable acid addition salts.

Examples of pharmaceutically acceptable cationic salts of the chemical compounds of the invention include, without limitation, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, choline, ricinium and the like of the chemical compounds of the invention containing anionic groups and Ammonium salts and the like. Such cationic salts can be formed by methods known and described in the art.

In the context of the present invention, "onium salts" of N-containing compounds have also been considered as pharmaceutically acceptable salts. Preferred "onium salts" include alkyl-onium salts, cycloalkyl-onium salts and cycloalkylalkyl-onium salts.

Examples of predrug or prodrug forms of the chemical compounds of the present invention include examples of suitable prodrugs of the substances according to the invention, including modified compounds in one or more reactive or derivatizable groups of the parent compound. Of particular interest are compounds modified from carboxyl groups, hydroxyl groups or amino groups. Examples of suitable derivatives are esters or amides.

The chemical compounds of the present invention may be provided in soluble or non-soluble form with pharmaceutically acceptable solvents (eg, water, ethanol, etc.). Soluble forms may also include hydrate forms (eg, monohydrate, dihydrate, hemihydrate, trihydrate and tetrahydrate, etc.). In general, soluble forms are considered equivalent to insoluble forms for the purposes of the present invention.

Stereoisomer

Those skilled in the art will appreciate that the compounds of the present invention may exist in different stereoisomeric forms, including enantiomers, diastereomers or sheet-trans isomers.

The present invention includes all such isomers and mixtures thereof, including racemic mixtures.

Racemic forms can be divided into optical antipodes by known methods and techniques. One method of separating enantiomeric compounds (including enantiomeric intermediates), where such chiral acid compounds are present, is to liberate the divided salts of diastereomers by treatment with an acid using an optically active amine. . Another method of partitioning racemates into optical enantiomers is based on chromatography on an optically active substrate. Accordingly, the racemic compounds of the present invention can be divided into their optical enantiomers by, for example, fractional crystallization of D- or L- (tartrate, mandelate or camphorsulfonate) salts.

The chemical compounds of the present invention are also optically active activated such as those derived from chemical compounds of the invention and (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) campanic acid. It is possible to divide by formation of diastereomeric amides by reaction of carboxylic acids or formation of diastereomeric carbamates by reaction of chemical compounds of the present invention with optically active chloroformate.

Additional methods of dividing optical isomers are known in the art. Such methods include those described in the literature. See Jaques J, Collet A, & Wilen S in " Enantiomers, Racemates , and Resolutions ", John Wiley and Sons, New York (1981).

Optically active compounds can also be prepared from optically active starting materials.

N-oxide

In the description of the present invention, N-oxides refer to oxide derivatives of tertiary amines, including nitrogen atoms of aromatic N-heterocyclic compounds, non-aromatic N-heterocyclic compounds, trialkylamines and trialkenylamines. For example, the N-oxide of the compound containing pyridyl may be a 1-oxy-pyridine-2, -3 or -4-yl derivative.

N-oxides of the compounds of the present invention can be prepared by oxidation of the corresponding nitrogen base using conventional oxidizing agents (e.g. hydrogen peroxide) in the presence of an acid (e.g. acetic acid) at elevated temperatures, or in a suitable solvent, e.g. dichloromethane. It can be prepared by reacting with peracid (eg peracetic acid) in ethyl acetate or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

Labeled compounds

The compounds of the present invention can be used in their labeled or unlabeled form. In the context of the present invention, a labeled compound has one or more atoms replaced by atoms having an atomic mass or mass number that is different from the atomic mass or mass number usually found. Labeling allows for easy quantitative detection of these compounds.

Labeled compounds of the invention may be useful for in vivo receptor imaging as monitoring agents in diagnostic instruments, radio tracers or various diagnostics.

The labeled isomers of the present invention preferably contain one or more radionuclides as labels. Positron emitting radionuclides are all candidates for use. In the context of the present invention, the radionuclide is preferably selected from ² H (deuterium), ³ H (tritium), ¹¹ C, ¹³ C, ¹⁴ C, ¹³¹ I, ¹²⁵ I, ¹²³ I and ¹⁸ F.

Physical methods for detecting labeled isomers of the present invention include: Position Emission Tomography (PET), Single Photon Imaging Computed Tomography (SPECT), Magnetic Resonance Spectroscopy (MRS) , Magnetic Resonance Imaging (MRI) and Computed Axial X-ray Tomography (CAT) or a combination thereof.

Manufacturing method

The chemical compounds of the present invention can be prepared by conventional chemical synthesis methods as shown in the Examples. Starting materials for the methods described herein can be readily prepared by conventional methods from known or commercially available compounds.

In addition, one compound of the present invention may be converted to another compound of the present invention using conventional methods.

The final product of the reaction described herein can be separated by conventional techniques (eg, extraction, crystallization, distillation, chromatography, etc.).

One skilled in the art can alternatively—and in some cases, in an easier way—perform the individual process steps mentioned above in a different order and / or complete the individual reactions in order to obtain the compounds of the present invention. It will be appreciated that it may be done in different steps in the route (ie, chemical modifications may be carried out in different intermediates for those associated with that particular reaction).

Biological activity

A representative pharmacological effect characterized by dopaminergic stabilizers is increased conduction of dopamine in the distal portion of the ascending dopaminertic process of the mammalian brain. This can be explained by measuring changes in biochemical indicators in the brain that have unique characteristics of dopamine antagonists, for example, by producing increased concentrations of dopamine metabolites such as 3,4-dihydroxyphenyl-acetic acid (DOPAC) in the striatum. Can be. Achievable conventional increases in DOPAC levels (progenitors) range from 350-400% of the control.

Representative compounds of the invention are shown in Table 1.

TABLE 1

ED ₅₀ value estimated for increase of DOPAC (3,4-dihydroxyphenylacetic acid) in rat striatum after systemic administration of test compound. See attached test for method and statistical calculations

The compounds according to the invention possess dopamine regulatory properties, and these and their pharmaceutical compositions are useful for the treatment of a number of central nervous system disorders, including psychological and neurological disorders. In particular, the compounds of the present invention and pharmaceutical compositions thereof can be used for the treatment of CNS disorders in which the dopaminergic system causes dysfunction due to direct or indirect causes.

The compounds and compositions according to the invention can be used to ameliorate all forms of psychosis, including schizophrenia, schizophrenia and bipolar disorder, as well as drug induced mental disorders. Righteous psychosis and hallucinations and non-human psychosis and hallucinations can also be treated.

In a preferred embodiment, the disease, disorder or condition contemplated according to the invention is a form of psychosis, in particular schizophrenia, schizophrenic disorder, bipolar disorder or drug induced mental disorder.

Mood and anxiety disorders, depression and obsessive compulsive disorders can also be treated with the compounds and compositions according to the invention.

Compounds that have a modulating effect on the dopaminergic system may be used to improve motor and cognitive function, as well as after brain injury, and to affect aging-related emotional disorders, neurodegenerative (such as dementia and aged cognitive impairment), and developmental disorders (such as autism). It can be used to treat categorical disorders, ADHD, cerebral palsy, Gilles de la Tourette's syndrome. Such brain damage can be induced by trauma, inflammation, infection, neoplasms, blood vessels, hypoxic or metabolic causes or by toxic reactions to foreign chemicals, where the foreign chemicals are used by drug abuse, pharmaceutical compounds and It is selected from the group consisting of environmental toxins.

The compounds and pharmaceutical compositions according to the invention can be used not only in conflict control disorders but also in behavioral disorders which are usually first diagnosed in infants, children or adolescents.

They can also be used to treat drug abuse disorders as well as disorders characterized by food misuse. They are further useful for the treatment of symptoms selected from the group consisting of sleep disorders, sexual disorders, eating disorders, obesity and headaches and other pains in the condition characterized by increased muscle tension.

Neurological treatments include the use of the compounds and their pharmaceutical compositions to improve mental and motor function in Parkinson's disease and related Parkinson's syndrome, dyskinesia (including L-DOPA induced dyskinesia) and dystonia. They can also be used to relieve tics and tremors of different origins. Moreover, they can be used to relieve pain in a condition characterized by increased muscle tension.

They can also be used for the treatment of Huntington's disease and other motor disorders as well as drug induced motor disorders. Narcolepsy as well as restless leg anxiety and related disorders can also be treated with compounds induced according to the invention.

The compounds according to the invention and their pharmaceutical compositions can be used for the treatment of Alzheimer's disease or related dementia disorders.

The effects of the compounds of the present invention on spontaneous exercise are shown in Table 2.

TABLE 2

Effect of Compounds of the Invention on Motor Activity in Drug-Pure Rats. Animals were placed in a mobility meter immediately after drug administration and motor activity was recorded for 60 minutes (count / 60 minutes ± SEM).

The effect of the compounds of the present invention on the increase in activity induced by direct or indirect dopaminergic agents, ie d-amphetamines and equivalents, is shown in Table 3.

TABLE 3

Effect of compounds of the present invention on the reduction of amphetamine-induced over-exercise. See the attached test for method and statistical calculations.

Pharmaceutical composition

In another aspect, the invention provides a novel pharmaceutical composition comprising a therapeutically effective amount of a chemical compound of the invention.

The present invention relates to pharmaceutical compositions comprising the compounds of the invention and their use in the treatment of CNS disorders. Both organic and inorganic acids can be used to form non-toxic pharmaceutically acceptable acid addition salts of the compounds according to the invention. Suitable acid addition salts of the compounds of the present invention include those formed with pharmaceutically acceptable salts such as those mentioned above. Pharmaceutical compositions comprising a compound according to the invention may also comprise substances used to facilitate the production or administration of the pharmaceutical preparations. Such materials are known to those skilled in the art and may be, for example, pharmaceutically acceptable auxiliaries, carriers and preservatives.

In clinical trials, the compounds according to the invention, together with pharmaceutically acceptable carriers, as free base or as pharmaceutically acceptable non-toxic acid addition salts (e.g. hydrochloride, lactate, acetate or sulfamate salts) In the form of pharmaceutical preparations comprising the active ingredient, it may be administered orally, rectally, intranasally or by injection. The carrier may be a solid, semisolid or liquid formulation. Usually, the active substance will comprise 0.1 to 99% by weight of the formulation, more particularly 0.5 to 20% by weight for the formulation intended for injection and 0.2 to 50% by weight for the formulation suitable for oral administration.

In order to prepare a pharmaceutical formulation containing a compound according to the invention in the form of an oral dosage unit, the selected compound may be a solid excipient such as lactose, saccharose, sorbitol, mannitol, starch (eg potato starch, corn starch or Amylopectin), cellulose derivatives], binders (e.g. gelatin or polyvinyl-pyrrolidine) and lubricants (e.g. magnesium stearate, calcium stearate, polyethylene glycol, wax and paraffin, etc.) and then compressed into tablets. Can be. If coating tablets are required, the core (prepared as described above) may be coated with a concentrated sugar solution, which may contain, for example, gum arabic, gelatin, talc, titanium dioxide and the like. Alternatively, tablets may be coated with polymers known to those skilled in the art, which are soluble in easy volatile organic solvents or mixtures of organic solvents. Dyestuffs can be added to these coatings to easily distinguish tablets containing different active materials or different amounts of active compounds.

To prepare soft gelatin capsules, the active substance can be mixed, for example with vegetable oil or polyethylene glycol. Hard gelatin capsules may be prepared by granulating the granules of the active substance using the excipients mentioned for tablets (e.g., lactose, saccharose, sorbitol, mannitol, starch (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin). It may contain. In addition, the liquid or semisolid of the drug may be filled with hard gelatin capsules.

Examples of tablet and capsule formulations suitable for oral administration are given below:

Tablet I mg / tablet

Compound 100

Lactose Ph. Eur 182.75

Croscarmellose Sodium 12.0

Corn Starch Paste (5% w / v Paste) 2.25

Magnesium Stearate 3.0

Tablets II mg / tablet

Compound 50

Lactose Ph. Eur 223.75

Croscarmellose Sodium 6.0

Corn Starch 15.0

Polyvinylpyrrolidone (5% w / v paste) 2.25

Magnesium Stearate 3.0

Tablets III mg / tablet

Compound 1.0

Lactose Ph. Eur 93.25

Croscarmellose Sodium 4.0

Corn Starch Paste (5% w / v Paste) 0.75

Magnesium Stearate 1.0

Capsule mg / capsules

Compound 10

Lactose Ph. Eur 488.5

Magnesium 1.5

The rectal dosage unit may be a liquid or suspension or may be prepared in the form of a suppository comprising the active substance in a mixture with a neutral fat base or a gelatin rectal capsule comprising the active substance in a mixture with vegetable or paraffin oils. can do. Oral liquid formulations may be in the form of syrups or suspensions, for example, solutions containing from about 0.2 to about 20% by weight of the active substance described herein, with the remainder being sugar and ethanol, water, glycerol and propylene glycol. Is a mixture of. Optionally, such liquid formulations may contain saccharin and carboxymethylcellulose as colorants, flavoring agents, thickening agents or other excipients known to those skilled in the art.

Parenteral solutions by injection may be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance, preferably at a concentration of 0.5 to about 10% by weight. These solutions may also contain stabilizers and / or buffers and may be provided in various dosage unit ampoules for convenience. Use and administration to the patient to be treated is readily apparent to those of ordinary skill in the art.

For intranasal administration or inhalation, the compounds of the present invention can be delivered in the form of solutions, anhydrous powders or suspensions. Dosing is via a pump spray vessel, or a pressurized vessel, which is compressed or pumped by the patient using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). It can occur via aerosol spray delivery from the nebulizer. The compounds of the present invention can also be administered via anhydrous powder inhalers as finely divided powders or as microspheres with a carrier material such as saccharides. Inhalers, pump nebulizers or aerosol nebulizers may be single or multiple doses. The dose can be adjusted via a valve that delivers a measurable amount of active compound.

The compounds of the present invention can also be administered in controlled release formulations. The compound is released at the rate necessary to maintain constant pharmacological activity for the desired time period. The dosage form provides a supply of the drug to the body for a period of time, thus maintaining the drug level in the therapeutic range for a longer time than conventional non-controlled formulations. The compounds may also be formulated in controlled release formulations to which release of the active compound is targeted. For example, the release of the compound may be limited to specific regions of the digestive system through the pH sensitivity of the formulation. Such formulations are known to those skilled in the art.

More details of techniques for formulation and administration can be found in the literature (the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, PA)).

Depending on the disorder to be treated and the patient and route of administration, the composition can be administered at various doses. The dose will also depend on the relationship of efficacy on absorbency and on the frequency and route of administration. The dose may be administered once, twice or three times a day or more. The compounds of the present invention necessarily vary depending on the body weight, sex and condition of the subject to be treated, the disease state to be treated and the particular route of administration selected, but the subject may be administered at a dose ranging from 0.01 to 500 mg / kg body weight per day. have. However, dose levels ranging from 0.1 to 10 mg / kg body weight per day, once or in divided doses, are most preferably used in humans in the treatment of disease. In addition, the dose level is such that a serum concentration of the compound of 0.1 nM to 10 μM is obtained.

Example

The invention is further illustrated as shown in the Examples and Schemes 1-4, which are not intended to limit the scope of the invention in any way.

Scheme 1

Scheme 2

Scheme 3

Scheme 4

Substituents in Schemes 1-4 are as follows: z is a leaving group, G ¹ is a group which may be modified to R ¹ or R ¹ , and A is an alkyl, hydrogen or protecting group. R ¹ , R ² , R ³ and R ⁴ are as defined above.

Example 1

N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -propan-1-amine

[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.4 g, 0.90 mmol), propan-1-amine (1 ml ) And ACN (3 ml) were heated at 120 ° C. for 30 minutes under microwave irradiation. Purification on SCX-3 column (TEA / MeOH) and small silica plug (DCM / MeOH). Yield: 0.2 g, 90%. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 223 ° C. MS m / z (relative intensity, 70 eV) 285 (M +, 5), 256 (4), 207 (5), 73 (5), 72 (bp).

Example 2

N-{[(2R) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -propan-1-amine

[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.7 g, 1.8 mmol), propane-1 A mixture of amine (1 ml) and ACN (3 ml) was heated at 120 ° C. for 20 minutes under microwave irradiation. Purification by SCX-3 column (TEA / MeOH) and flash column chromatography (EtOAc / MeOH). Yield: 0.4 g, 73%. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 228 ° C. MS m / z (relative intensity, 70 eV) 285 (M +, 3), 207 (4), 73 (5), 72 (bp), 70 (5). [α] = + 67 ° (MeOH).

Example 3

N-{[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -propan-1-amine

[(2R) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.4 g, 0.9 mmol), propane-1 A mixture of amine (1 ml) and ACN (3 ml) was heated at 120 ° C. for 20 minutes under microwave irradiation. Purification on SCX-3 column (TEA / MeOH) and small silica plug (DCM / MeOH). Yield: 0.2 g, 90%. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 228 ° C. MS m / z (relative intensity, 70 eV) 285 (M +, 2), 79 (3), 73 (5), 72 (bp), 70 (5). [α] = − 73 ° (MeOH).

Example 4

N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine

[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.7 g, 1.8 mmol), ethanamine (1 ml, in water 70%) and ACN (3 ml) were heated at 120 ° C. for 30 minutes under microwave irradiation. Purification was performed on flash column chromatography and SCX-3 columns (TEA / MeOH). Yield: 0.4 g, 72%. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 261 ° C. MS m / z (relative intensity, 70 eV) 271 (M +, 19), 226 (4), 207 (9), 79 (6), 58 (bp).

Example 5

N-{[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine

[(2R) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (1.0 g, 2.51 mmol), ethanamine ( 2 ml, 70% in water) and ACN (6 ml) were heated at 120 ° C. for 20 minutes under microwave irradiation. Purification by SCX-3 column (TEA / MeOH) and flash column chromatography (isooctane / EtOAc / MeOH). Yield: 0.53 g, 78%. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 271 ° C. MS m / z (relative intensity, 70 eV) 271 (M +, 29), 58 (100), 59 (10), 272 (7), 79 (5). [α] = − 66 ° (MeOH).

Example 6

1-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} piperidine

[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.6 g, 1.5 mmol), piperidine (1 ml) and The mixture of ACN (3 ml) was heated at 120 ° C. for 20 minutes under microwave irradiation. Purification was performed by flash chromatography over an SCX-3 column (TEA / MeOH) and a small silica plug (DCM / MeOH, 5:95). Yield: 0.4 g, 85%. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 248 ° C. MS m / z (relative intensity, 70 eV) 311 (M +, 1), 310 (M +, 2), 207 (3), 99 (7), 98 (bp).

Example 7

1-{[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} piperidine

[(2R) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.4 g, 1 mmol), piperidine ( 1 ml) and ACN (3 ml) to prepare according to Example 3. Yield: 0.3 g, 94%. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 227 ° C. MS m / z (relative intensity, 70 eV) 311 (M +, 1), 310 (M +, 1), 99 (7), 98 (bp), 79 (2), 55 (4). [α] = − 65 ° (MeOH).

Example 8

1-{[(2R) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} piperidine

[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.5 g, 1.1 mmol), piperidine (1 ml) and ACN (3 ml) were heated at 120 ° C. for 20 minutes under microwave irradiation. Purification was performed by flash chromatography using an SCX-3 column (TEA / MeOH) and eluent first (DCM / MeOH) and then eluent (EtOAc / MeOH). Yield: 0.2 g, 72%. The amine was converted to hydrochloride and crystallized from EtOH / Et ₂ O. Mp 226 ° C. MS m / z (relative intensity, 70 eV) 311 (M +, 1), 310 (M +, 1), 99 (7), 98 (bp), 79 (2), 55 (4). [α] = + 62 ° (MeOH).

Example 9

N-methyl-1- [7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methanamine

[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.4 g, 0.9 mmol), methanamine (33% in EtOH , 1 ml) and ACN (3 ml). Yield: 0.2 g, 76%. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 273 ° C. MS m / z (relative intensity, 70 eV) 257 (M +, 79), 79 (bp), 70 (70), 63 (59), 51 (83).

10 to implementation

N-methyl-1-[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxyn-2-yl] methanamine

[(2R) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.4 g, 1 mmol), methanamine (EtOH 33% in 1 ml) and ACN (3 ml) were prepared according to Example 3. Yield: 0.2 g, 89%. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 248 ° C. MS m / z (relative intensity, 70 eV) 257 (M +, bp), 79 (86), 70 (59), 63 (50), 51 (71). [α] = − 59 ° (MeOH).

11 to implementation

1-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} pyrrolidine

[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.4 g, 0.9 mmol), pyrrolidine (1 ml) and The mixture of ACN (3 ml) was heated at 120 ° C. for 20 minutes under microwave irradiation. Purification twice on SCX-3 column (TEA / MeOH) and flash column chromatography (isooctane / EtOAc / MeOH). Yield: 0.2 g, 75%. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 221 ° C. MS m / z (relative intensity, 70 eV) 297 (M +, 1), 85 (6), 84 (bp), 79 (2), 55 (4).

12 to implementation

3-methyl-1-{[(2R) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} piperidine

[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.20 g, 0.5 mmol), 3-methyl A mixture of piperidine (0.35 ml, 3 mmol) and ACN (2 ml) was heated at 120 ° C. for 30 minutes under microwave irradiation. Purification was performed on flash column chromatography (isooctane / EtOAc / MeOH). Yield: 0.097 g, 85%. The amine was converted to fumaric acid salt and crystallized from MeOH / (i-Pr) ₂ O. Mp 159 ° C. MS m / z (relative intensity, 70 eV) 325 (M +, 1), 113 (83), 112 (bp), 69 (43), 55 (46). [α] = + 50 ° (MeOH).

Example 13

2-methyl-N-{[(2R) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine

[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.2 g, 0.5 mmol), 2-methyl A mixture of propan-1-amine (1 ml) and ACN (2 ml) was heated at 120 ° C. for 30 minutes under microwave irradiation. Purification by SCX-3 column (TEA / MeOH) and flash column chromatography (EtOAc / MeOH). Yield: 0.1 g, 77%. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 213 ° C. MS m / z (relative intensity, 70 eV) 299 (M +, 4), 256 (16), 207 (11), 86 (bp), 57 (8). [α] = + 65 ° (MeOH).

Example 14

2-methyl-N-{[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine

[(2R) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.19 g, 0.48 mmol), 2-methyl A mixture of propan-1-amine (0.9 ml) and ACN (3 ml) was heated at 120 ° C. for 20 minutes under microwave irradiation. Purification on SCX-3 column (TEA / MeOH) and flash column chromatography (DCM / MeOH). Yield: 0.11 g, 74%. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 214 ° C. MS m / z (relative intensity, 70 eV) 299 (M +, 6), 86 (100), 256 (21), 57 (8), 70 (6). [α] = − 58 ° (MeOH).

Example 15

N-methyl-N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine

[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.175 g, 0.44 mmol), N-methylpropane-1- Prepared according to Example 14 using amine (0.35 ml) and ACN (2 ml). Yield: 0.11 g, 84%. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 222 ° C. MS m / z (relative intensity, 70 eV) 299 (M +, 1) 86 (100), 58 (8), 84 (6), 87 (6).

Example 16

N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-propylpropan-1-amine

[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.175 g, 0.44 mmol), N-propylpropane-1- Prepared according to Example 14 using amine (1 ml) and ACN (3 ml). Yield: 0.11 g, 77%. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 182 ° C. MS m / z (relative intensity, 70 eV) 327 (M +, 1) 114 (100), 298 (17), 115 (8), 86 (6).

Example 17

N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-propan-1-amine

[5-Fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.3 g, 0.7 mmol), propane- Prepared according to Example 5 using 1-amine (1 ml) and ACN (2 ml). Yield: 0.2 g, 70%. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 198 ° C. MS m / z (relative intensity, 70 eV) 303 (M +, 10), 281 (38), 207 (85), 72 (bp), 70 (39).

Example 18

N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine

[5-Fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.3 g, 0.8 mmol), ethanamine (1 ml, 70% in water) and ACN (2 ml) were heated at 120 ° C. for 20 minutes under microwave irradiation. Purification on SCX-3 column (TEA / MeOH) and flash column chromatography (isooctane / EtOAc / MeOH). Yield: 0.1 g, 61%. The amine was converted to hydrochloride and crystallized from EtOH. Mp 256 ° C. MS m / z (relative intensity, 70 eV) 289 (M +, 12), 70 (17), 59 (20), 58 (bp), 56 (19).

Example 19

N-{[(2S) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine

[(2R) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.56 g, 1.33 mmol ), Ethanamine (1 ml, 70% in water) and ACN (3 ml) were prepared according to Example 5. Yield: 0.32 g, 83%. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 274 ° C. MS m / z (relative intensity, 70 eV) 289 (M +, 3), 70 (3), 59 (4), 58 (bp), 56 (3). [α] = − 58 ° (MeOH).

Example 20

1- [5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] -N-methylmethanamine

[5-Fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.4 g, 1 mmol), methanamine ( 1 ml, 40% in water) and ACN (3 ml) were heated at 120 ° C. for 20 minutes under microwave irradiation. Purification by flash column chromatography (EtOAc / MeOH) afforded the title compound. Yield: 0.2 g, 69%. The amine was converted to hydrochloride and crystallized from EtOH / Et ₂ O. Mp 243 ° C. MS m / z (relative intensity, 70 eV) 275 (M +, 81), 97 (48), 70 (bp), 69 (73), 63 (58).

Example 21

N-{[(2S) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine

N-benzyl-N-{[(2S) -8-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propane-1- To a mixture of amine (0.36 g, 0.97 mmol), methanol (5 ml) and Pd / C (0.1 g) was added dropwise triethylsilane (4,7 ml, 30 mmol) under N ₂ . The solution was stirred for 16 h at room temperature and filtered through celite. The solvent was evaporated to dryness. Purification by flash column chromatography (isooctane / EtOAc / -Et ₃ N) afforded the title compound. Yield: 0.12 g, 41%. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 226 ° C. MS m / z (relative intensity, 70 eV) 303 (M +, 4), 274 (7), 73 (5), 72 (bp), 70 (8). [α] = − 60 ° (MeOH).

Example 22

N-{[(2S) -7- (trifluoromethylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine

[(2R) -7- (trifluoromethylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl-4-methylbenzenesulfonate (0.27 g, 0.68 mmol) Prepared according to Example 2 using ethanamine (1 ml, 70% in water) and ACN (2 ml). Yield: 0.170 g, 76%. The amine was converted to hydrochloride and recrystallized from acetonitrile. Mp 208 ° C. MS m / z (relative intensity, 70 eV) 325 (M +, 1) 58 (bp), 56 (8), 79 (5), 59 (4). [a] = -40 ° (MeOH).

Example 23

N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} -N-propan-1-amine

[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl 4-methylbenzenesulfonate (0.30 g, 0.75 mmol), propan-1-amine (1 ml) and aceto The mixture of nitrile (5 ml) was stirred at reflux overnight. Purification was by SCX-3 column (TEA / MeOH) and preparative HPLC (MeOH / NH ₃ buffer). Yield: 0.19 g, 89%. The amine was converted to hydrochloride and recrystallized from acetonitrile. Mp 214 ° C. MS m / z (relative intensity, 70 eV) 283 (M < + >, 12), 254 (12), 131 (6), 73 (5), 72 (bp).

Example 24

N-{[(2S) -7- (trifluoromethylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine

[(2R) -7- (trifluoromethylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl-4-methylbenzenesulfonate (0.39 g, 0.98 mmol) Prepared according to Example 2 using Propan-1-amine (1 ml) and ACN (2 ml). Yield: 0.150 g, 45%. The amine was converted to hydrochloride and recrystallized from acetonitrile. Mp 175 ° C. MS m / z (relative intensity, 70 eV) 339 (M +, 2) 310 (10), 270 (6), 72 (bp), 70 (6). [α] = + 50 ° (MeOH).

Example 25

N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} prop-2-en-1-amine

[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), prop-2-ene- The mixture of 1-amine (0.5 ml) and ACN (3 ml) was heated at 120 ° C. for 20 minutes under microwave irradiation. MS m / z (relative intensity, 70 eV) 283 (M +, 4), 79 (4), 71 (6), 70 (bp), 68 (4).

Example 26

4-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} morpholine

[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), morpholine (0.5 ml) and Prepared according to Example 25 using ACN (3 ml). MS m / z (relative intensity, 70 eV) 313 (M +, 1), 101 (6), 100 (bp), 70 (2), 56 (4).

Example 27

N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} butan-1-amine

[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), butan-1-amine (0.5 ml) and ACN (3 ml) to prepare according to Example 25. MS m / z (relative intensity, 70 eV) 299 (M +, 6), 256 (5), 87 (6), 86 (bp), 70 (5).

Example 28

N, N-dimethyl-N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methanamine

[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), N-methylmethanamine (0.5 ml) and ACN (3 ml) to prepare according to Example 25. MS m / z (relative intensity, 70 eV) 271 (M +, 1), 84 (2), 79 (3), 59 (4), 58 (bp).

Example 29

N-ethyl-N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine

[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), N-ethylethanamine (0.5 ml) and ACN (3 ml) to prepare according to Example 25. MS m / z (relative intensity, 70 eV) 299 (M +, 1), 87 (6), 86 (bp), 84 (2), 58 (5).

Example 30

N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-2-amine

[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), propan-2-amine (0.5 ml) and ACN (3 ml) to prepare according to Example 25. MS m / z (relative intensity, 70 eV) 211 (34), 139 (4), 98 (5), 70 (7), 58 (bp).

Example 31

N-ethyl-N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-propan-1-amine

[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), N-ethylpropane-1- Prepared according to Example 25 using amine (0.5 ml) and ACN (3 ml). MS m / z (relative intensity, 70 eV) 299 (M +, 2), 270 (9), 87 (6), 86 (bp), 58 (7).

Example 32

2-({[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} amino) ethanol

[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), 2-aminoethanol (0.5 ml ) And ACN (3 ml). ¹ H-NMR (400 MHz, CD ₃ OD): δ 7.47 (1 H, d, J 2), δ 7.42 (1 H, dd, J 8, 2), δ 7.07 (1 H, d, J 8.0) , δ 4.43 (1 H, dd, J 12, 2.4), δ 4.37 (1 H, m), δ 4.09 (1 H, dd J 12, 7.2), δ 3.68 (2H, t, J 5.6), δ 3.07 (3H, s), δ 2.94 (2H, m), 2.80 (2H, m) ppm (J-value is expressed as shift to solvent-peak at 3.31 ppm in Hz).

Example 33

N-methyl-N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine

[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), N-methylethanamine (0.5 ml) and ACN (3 ml) to prepare according to Example 25. MS m / z (relative intensity, 70 eV) 285 (M +, 1), 84 (2), 79 (2), 73 (5), 72 (bp).

Example 34

2-methoxy-N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine

[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), 2-methoxyethanamine ( 0.5 ml) and ACN (3 ml) were prepared according to Example 25. MS m / z (relative intensity, 70 eV) 301 (M +, 2), 256 (19), 88 (bp), 56 (12), 58 (7).

Example 35

1-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} azetidine

[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), 2-azetidine (0.1 ml ) And ACN (3 ml). MS m / z (relative intensity, 70 eV) 283 (M +, 1), 79 (3), 71 (5), 70 (bp), 51 (3).

Example 36

2-methyl-N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine

[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), 2-methylpropane-1- Prepared according to Example 25 using amine (0.5 ml) and ACN (3 ml). MS m / z (relative intensity, 70 eV) 299 (M +, 6), 256 (20), 86 (bp), 70 (6), 57 (8).

Example 37

N-{[(2S) -8-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine

N-benzyl-N-{[(2S) -8-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl}, ethanamine ( Prepared according to Example 21 using 0.95 g, 2.5 mmol), methanol (5 ml), Pd / C (0.2 g) and triethylsilane (12 ml, 75 mmol). Yield 0.27 g, 37%. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 270 ° C. MS m / z (relative intensity, 70 eV) 289 (M +, 5), 97 (4), 69 (4), 58 (bp), 56 (5). [α] = − 64 ° (MeOH).

Example 38

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine

[(2R) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.47 g, 1.09 mmol) Prepared according to Example 5 using ethanamine (1 ml, 70% in water) and ACN (7 ml). Yield: 0.278 g, 83%. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 267 ° C. MS m / z (relative intensity, 70 eV) 305 (M +, 4), 63 (3), 59 (4), 58 (bp), 56 (5). [α] = − 62 ° (MeOH).

Example 39

N-{[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N- (3,3,3-trifluoro Propyl) amine

[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methylamine (0.31 g, 1.27 mmol), 1,1,1-trifluoro A mixture of rho-3-iodopropane (0.16 ml, 1.4 mmol), K ₂ CO ₃ (0.35 g, 2.5 mmol) and ACN (4 ml) was heated at 120 ° C. under microwave irradiation for 40 minutes. The product was evaporated to dryness and purified by preparative HPLC (MeOH / NH ₃ buffer). Yield: 0.19 g, 44%. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp204 ° C. MS m / z (relative intensity, 70 eV) 339 (M +, 3), 127 (5), 126 (bp), 79 (4), 51 (4). [α] = − 52 ° (MeOH).

Example 40

N-{[(2S) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N- (3,3, 3-trifluoropropyl) amine

1-[(2S) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methanamine (0.3 g, 1.1 mmol), 1 A mixture of 1,1-trifluoro-3-iodopropane (0.16 ml, 1.4 mmol), K ₂ CO ₃ (0.32 g, 2.3 mmol) and ACN (4 ml) was subjected to microwave irradiation at 120 ° C. for 30 minutes. Heated. The mixture was filtered, evaporated to dryness and the product purified by flash column chromatography (EtOAc). Yield: 0.12 g, 31%. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 233 ° C. MS m / z (relative intensity, 70 eV) 357 (M +, 1), 274 (3), 127 (5), 126 (bp), 69 (3). [α] = − 53 ° (MeOH).

Example 41

1-[(2S) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] -N-methylmethanamine

[(2R) -7- (trifluoromethyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.7 g, 1.7 mmol), methanamine (1 ml, 40% in water) and ACN (3 ml) were heated at 120 ° C. for 20 minutes under microwave irradiation. The mixture was evaporated to dryness and the product was purified by flash column chromatography (EtOAc / MeOH). Yield 0.31 g, 65%. The amine was converted to hydrochloride and crystallized from EtOH / MeOH / Et ₂ O. Mp 260 ° C. MS m / z (relative intensity, 70 eV) 275 (M < + >, 57), 97 (50), 70 (bp), 69 (80), 63 (58). [α] = − 60 ° (MeOH).

Example 42

N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} prop-2-en-1-amine

[5-Fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), pro A mixture of phen-2-en-1-amine (0.5 ml) and ACN (2.5 ml) was heated at 120 ° C. for 20 minutes under microwave irradiation. MS m / z (relative intensity, 70 eV) 301 (M +, 2), 71 (5) 70 (bp), 69 (4) 68 (5).

Example 43

4-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} morpholine

[5-Fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), mor Prepared according to Example 42 using Pauline (0.5 ml) and ACN (2.5 ml). MS m / z (relative intensity, 70 eV) 331 (M +, 1), 101 (5), 100 (bp), 98 (4), 56 (5).

Example 44

N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} butan-1-amine

[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), butane Prepared according to Example 42 using -1-amine (0.5 ml) and ACN (2.5 ml). MS m / z (relative intensity, 70 eV) 317 (M +, 2), 274 (7), 87 (6), 86 (bp), 70 (6).

Example 45

N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-propylpropan-1-amine

[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), N Prepared according to Example 42 using propylpropan-1-amine (0.5 ml) and ACN (2.5 ml). MS m / z (relative intensity, 70 eV) 345 (M +, 0.5), 316 (21), 115 (8), 114 (bp), 112 (6).

Example 46

1- [5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] -N, N-dimethylmethanamine

[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), N Prepared according to Example 42 using methylmethanamine (0.5 ml, 2.0 M in MeOH) and ACN (2.5 ml). MS m / z (relative intensity, 70 eV) 289 (M +, 1), 84 (2), 69 (2), 59 (3), 58 (bp).

Example 47

N-ethyl-N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine

[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), N Prepared according to Example 42 using ethylethanamine (0.5 ml) and ACN (2.5 ml). MS m / z (relative intensity, 70 eV) 317 (M +, 0.2), 87 (6), 86 (bp), 58 (5), 56 (3).

Example 48

N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-2-amine

[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), propane Prepared according to Example 42 using 2-amine (0.5 ml) and ACN (2.5 ml). MS m / z (relative intensity, 70 eV) 303 (M +, 2), 288 (17), 84 (6), 72 (bp), 56 (6).

Example 49

N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-methylpropan-1-amine

[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), N Prepared according to Example 42 using -methyl-propan-1-amine (0.5 ml) and ACN (2.5 ml). MS m / z (relative intensity, 70 eV) 317 (M +, 0.5), 288 (8), 86 (bp), 84 (6), 58 (8).

Example 50

N-ethyl-N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine

[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), N Prepared according to Example 42 using ethylpropan-1-amine (0.5 ml) and ACN (2.5 ml). MS m / z (relative intensity, 70 eV) 331 (M +, 0.5), 101 (7), 100 (bp), 98 (8), 58 (8).

Example 51

2-({[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} amino) ethanol

[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), 2 Prepared according to Example 42 using aminoethanol (0.5 ml) and ACN (2.5 ml). ¹ H-NMR (400 MHz, MeOD): δ 7.36 (2H, m), δ 4.54 (1 H, dd, J 12, 2.4), δ 4.44 (1 H, m), δ 4.18 (1 H, dd, J 12, 7.2), δ 3.71 (2H, t, J 5.6), δ 3.13 (3H, s), δ 2.98 (2H, m), 2.81 (2H, m) ppm (J-value is 3.31 ppm solvent- Shift to peak (in Hz)).

Example 52

N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-methylethanamine

[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), N Prepared according to Example 42 using methylethanamine (0.5 ml) and ACN (1 ml). MS m / z (relative intensity, 70 eV) 303 (M +, 0.5), 84 (2), 73 (4), 72 (bp), 69 (2).

Example 53

N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -2-methoxyethanamine

[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), 2 Prepared according to Example 42 using methoxyethanamine (0.5 ml) and ACN (2.5 ml). MS m / z (relative intensity, 70 eV) 319 (M +, 1), 274 (23), 88 (bp), 70 (8), 56 (13).

Example 54

1-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} azetidine

[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), aze Prepared according to Example 42 using Tidine (0.1 ml) and ACN (2.5 ml). MS m / z (relative intensity, 70 eV) 301 (M +, 1), 244 (3), 71 (5), 70 (bp), 69 (4).

Example 55

N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -2-methylpropan-1-amine

[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), 2 Prepared according to Example 42 using -methylpropan-1-amine (0.5 ml) and ACN (2.5 ml). MS m / z (relative intensity, 70 eV) 317 (M < + >, 2), 274 (38), 86 (bp), 70 (8), 57 (8).

Example 56

1-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} pyrrolidine

[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), p Prepared according to Example 42 using Rollidine (0.5 ml) and ACN (2.5 ml). MS m / z (relative intensity, 70 eV) 315 (M +, 0.7), 110 (3), 85 (6), 84 (bp), 55 (4).

Example 57

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} prop-2-ene-1- Amine

[(2R) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol) , A mixture of prop-2-en-1-amine (0.5 ml) and ACN (3 ml) was heated at 120 ° C. for 20 minutes under microwave irradiation. MS m / z (relative intensity, 70 eV) 317 (M +, 2), 113 (3), 71 (5), 70 (bp), 68 (3) 63 (3).

Example 58

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} butan-1-amine

[(2R) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol) Prepared according to Example 57, using butan-1-amine (0.5 ml) and ACN (3 ml). MS m / z (relative intensity, 70 eV) 333 (M +, 2), 290 (6), 87 (7), 86 (bp), 85 (4), 70 (7).

Example 59

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-propylpropan-1-amine

[(2R) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol) Prepared according to Example 57 using N-propylpropan-1-amine (0.5 ml) and ACN (3 ml). MS m / z (relative intensity, 70 eV) 361 (M +, 0.2), 332 (6), 115 (9), 114 (bp), 86 (7), 72 (4).

Example 60

1-[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] -N, N-dimethylmethanamine

[(2R) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol) Prepared according to Example 57 using N-methylmethanamine (0.5 ml, 2.0 M in MeOH) and ACN (3 ml). MS m / z (relative intensity, 70 eV) 305 (M +, 0.4), 85 (2), 84 (3), 63 (2), 59 (4), 58 (bp).

Example 61

N-ethyl-N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine

[(2R) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol) Prepared according to Example 57 using N-ethylethanamine (0.5 ml) and ACN (3 ml). MS m / z (relative intensity, 70 eV) 333 (M +, 0.2), 98 (3), 87 (7), 86 (bp), 58 (6), 56 (3).

Example 62

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-2-amine

[(2R) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol) Prepared according to Example 57 using Propan-2-amine (0.5 ml) and ACN (3 ml). MS m / z (relative intensity, 70 eV) 319 (M +, 1), 304 (8), 84 (8), 73 (6), 72 (bp), 56 (7).

Example 63

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-methylpropan-1-amine

[(2R) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol) Prepared according to Example 57 using N-methyl-propan-1-amine (0.5 ml) and ACN (3 ml). MS m / z (relative intensity, 70 eV) 333 (M +, 0.3), 304 (4), 87 (6), 86 (bp), 84 (7), 58 (10).

Example 64

N-ethyl-N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine

[(2R) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol) Prepared according to Example 57, using N-ethylpropan-1-amine (0.5 ml) and ACN (3 ml). MS m / z (relative intensity, 70 eV) 347 (M +, 0.2), 101 (7), 100 (bp), 98 (5), 72 (8), 58 (9).

Example 65

2-({[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} amino) ethanol

[(2R) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol) Prepared according to Example 57, using 2-aminoethanol (0.5 ml) and ACN (3 ml). ¹ H-NMR (400 MHz, MeOD): δ 7.57 (1 H, d, J 2.3), δ 7.46 (1 H, d, J 2.3), δ 4.59 (1 H, dd, J 11.6, 2.4), δ 4.42 (1 H, m), δ 4.21 (1 H, dd, J 11.6, 7.4), δ 3.71 (2H, t, J 5.3), δ 3.14 (3H, s), δ 2.97 (2H, d, J 5.8 ), δ 2.82 (3H, m) ppm (J-value is expressed as shift (Hz) for solvent-peak at 4.8 ppm).

Example 66

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-methylethanamine

[(2R) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol) Prepared according to Example 57 using N-methylethanamine (0.5 ml) and ACN (3 ml). MS m / z (relative intensity, 70 eV) 319 (M +, 0.3), 85 (3), 84 (3), 73 (5), 72 (bp), 63 (2).

Example 67

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -2-methoxyethanamine

[(2R) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol) Prepared according to Example 57, using 2-methoxyethanamine (0.5 ml) and ACN (3 ml). MS m / z (relative intensity, 70 eV) 335 (M +, 1), 290 (18), 88 (bp), 70 (8), 58 (8), 56 (12).

Example 68

1-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} azetidine

[(2R) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol) Prepared according to Example 57, using azetidine (0.1 ml) and ACN (3 ml). MS m / z (relative intensity, 70 eV) 317 (M +, 1), 85 (3), 71 (5), 70 (bp), 68 (2), 63 (3).

Example 69

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -2-methylpropan-1-amine

[(2R) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol) Prepared according to Example 57 using 2-methylpropan-1-amine (0.5 ml) and ACN (3 ml). MS m / z (relative intensity, 70 eV) 333 (M +, 2), 292 (8), 290 (20), 86 (bp), 70 (8), 57 (9).

Example 70

1-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} pyrrolidine

[(2R) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol) Prepared according to Example 57 using Pyrrolidine (0.5 ml) and ACN (3 ml). MS m / z (relative intensity, 70 eV) 331 (M +, 0.4), 110 (4), 85 (8), 84 (bp), 63 (2), 55 (5).

Example 71

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -propan-1-amine

[(2R) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol) Prepared according to Example 57 using Propan-1-amine (0.5 ml) and ACN (3 ml). MS m / z (relative intensity, 70 eV) 319 (M +, 1), 85 (3), 73 (5), 72 (bp), 70 (7), 63 (3).

Example 72

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -3-fluoropropane-1- Amine

3-fluoropropan-1-amine HCl-salt (0.178 g, 1.52 mmol) was basified on an SCX-3 ion exchange column (TEA / MeOH). [(2R) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol) And 3-fluoropropan-1-amine (0.15 M in MeOH / TEA: 4/1, 5 ml) were heated at 120 ° C. under microwave irradiation for 1 hour 20 minutes. MS m / z (relative intensity, 70 eV) 337 (M +, 0.4), 91 (5), 90 (bp), 85 (3), 70 (17), 63 (3).

Example 73

N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -2,2-dimethylpropane-1 -Amine

[(2R) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol) Prepared according to Example 57, using 2,2-dimethylpropan-1-amine (0.5 ml) and ACN (3 ml). MS m / z (relative intensity, 70 eV) 347 (M +, 2), 332 (20), 292 (30), 290 (78), 100 (bp), 70 (16).

Example 74

1-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} piperidine

[(2R) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.49 g, 1.1 mmol) , A mixture of piperidine (1 ml, 10.1 mmol) and MeOH (2 ml) was heated at 120 ° C. under microwave irradiation for 25 minutes. Purification by SCX-3 column (TEA / MeOH) and flash column chromatography (MeOH / EtOAc) gave the title compound (0.31 g). The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O (0.25 g). MS m / z (relative intensity, 70 eV) 345 (M +, 0.5), 124 (3), 99 (7), 98 (bp), 96 (2), 55 (4) [α] = -60 ° ( MeOH).

Example 75

1-[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] -N-methylmethanamine

[(2R) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.48 g, 1.1 mmol) , A mixture of methaneamine (1.5 ml, 33% in EtOH, 4 mmol) and ACN (3 ml) was heated at 120 ° C. for 20 minutes under microwave irradiation. Purification by SCX-3 column (TEA / MeOH) and flash column chromatography (MeOH / EtOAc) gave the title compound (0.18 g). The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 262 ° C. MS m / z (relative intensity, 70 eV) 291 (M +, 43), 113 (57), 85 (80), 70 (bp), 63 (84), 50 (60) [α] = -61 ° ( MeOH).

Example 76

N-{[(2S) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -propan-1-amine

[(2R) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.2 g, 0.5 mmol ), Propane-1-amine (1 ml) and ACN (3 ml) were heated at 120 ° C. for 20 minutes under microwave irradiation. Purification by SCX-3 column (TEA / MeOH) and flash chromatography (isooctane / EtOAc / MeOH). Yield: 0.12 g, 79%. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 192 ° C. MS m / z (relative intensity, 70 eV) 303 (M +, 2), 73 (5), 72 (bp), 70 (11), 69 (7), 63 (5). [α] = − 64 ° (MeOH).

Example 77

2,2-dimethyl-N-{[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine

[(2R) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.196 g, 0.5 mmol), 2,2 A mixture of dimethylpropan-1-amine (1 ml, 8.5 mmol) and ACN (3 ml) was heated at 120 ° C. for 20 minutes under microwave irradiation. Purification by SCX-3 column (TEA / MeOH) and flash chromatography (EtOAc) gave the title compound. Yield: 0.1 g. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 242 ° C. MS m / z (relative intensity, 70 eV) 313 (M +, 6), 298 (32), 257 (14), 256 (bp), 207 (12), 100 (92). [α] = − 53 ° (MeOH).

Example 78

N-methyl-1- [7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methanamine

[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), Methanamine (33% in EtOH, 0.5 ml ) And ACN (3 ml). MS m / z (relative intensity, 70 eV) 255 (M +, 92), 132 (52), 131 (bp), 77 (76), 70 (48).

Example 79

N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} ethanamine

[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), ethanamine (2.0 M in MeOH, 0.5 ml ) And ACN (3 ml). MS m / z (relative intensity, 70 eV) 269 (M +, 5), 131 (6), 77 (6), 58 (bp), 56 (4).

Example 80

N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} prop-2-en-1-amine

[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), prop-2-en-1-amine Prepared according to Example 25 using (0.5 ml) and ACN (3 ml). MS m / z (relative intensity, 70 eV) 281 (M +, 6), 131 (8), 77 (6), 71 (5), 70 (bp).

Example 81

4-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} morpholine

[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), morpholine (0.5 ml) and ACN (3 ml ) Was prepared according to Example 25. MS m / z (relative intensity, 70 eV) 311 (M +, 2), 132 (3), 131 (5), 101 (6), 100 (bp), 56 (6).

Example 82

N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} butan-1-amine

[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), butan-1-amine (0.5 ml) and Prepared according to Example 25 using ACN (3 ml). MS m / z (relative intensity, 70 eV) 297 (M +, 6), 254 (9), 131 (8), 87 (7), 86 (bp), 77 (7).

Example 83

N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} -N-propylpropan-1-amine

[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), N-propylpropan-1-amine (0.5 ml) and ACN (3 ml) to prepare according to Example 25. MS m / z (relative intensity, 70 eV) 325 (M +, 1), 296 (7), 131 (4), 115 (10), 114 (bp), 86 (6).

Example 84

N, N-dimethyl-1- [7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methanamine

[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), N-methylmethanamine (2.0 M in MeOH , 0.5 ml) and ACN (3 ml) were prepared according to Example 25. MS m / z (relative intensity, 70 eV) 269 (M +, 2), 131 (4), 77 (4), 63 (2), 59 (4), 58 (bp).

Example 85

N-ethyl-N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} ethanamine

[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), N-ethylethanamine (0.5 ml) and Prepared according to Example 25 using ACN (3 ml). MS m / z (relative intensity, 70 eV) 297 (M +, 1), 131 (4), 87 (6), 86 (bp), 58 (5), 56 (3).

Example 86

N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} propan-2-amine

[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), propan-2-amine (0.5 ml) and Prepared according to Example 25 using ACN (3 ml). MS m / z (relative intensity, 70 eV) 283 (M < + >, 6), 268 (8), 77 (7), 72 (bp), 56 (6).

Example 87

N-methyl-N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} propan-1-amine

[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), N-methylpropan-1-amine (N Prepared according to Example 25 using -N-) (0.5 ml) and ACN (3 ml). MS m / z (relative intensity, 70 eV) 297 (M +, 2), 131 (5), 87 (6), 86 (bp), 77 (5), 58 (7).

Example 88

N-ethyl-N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} propan-1-amine

[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), N-ethylpropan-1-amine (0.5 ml) and ACN (3 ml) to prepare according to Example 25. MS m / z (relative intensity, 70 eV) 311 (M +, 1), 282 (5), 101 (8), 100 (bp), 72 (6), 58 (9).

Example 89

2-({[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} amino) ethanol

[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), 2-aminoethanol (0.5 ml) and ACN Prepared according to Example 25 using (3 ml). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.37-7.39 (2H, m), δ 7.23 (1 H, d, J 8 Hz), δ 4.18-4.24 (1 H, m), δ 3.63-3.72 (2H), δ 3.02 (3H, s), δ 2.81-3.00 (6H, m), δ 1.97-2.08 (1 H, m), δ 1.83-1.87 (1 H, m).

Example 90

N-methyl-N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} ethanamine

[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), N-methylethanamine (0.5 ml) and Prepared according to Example 25 using ACN (3 ml). MS m / z (relative intensity, 70 eV) 283 (M +, 2), 131 (4), 77 (4), 73 (5), 72 (bp), 63 (2).

Example 91

2-methoxy-N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} ethanamine

[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), 2-methoxyethanamine (0.5 ml) And ACN (3 ml) to prepare according to Example 25. MS m / z (relative intensity, 70 eV) 299 (M +, 6), 254 (38), 131 (8), 88 (bp), 58 (8), 56 (12).

Example 92

1-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} azetidine

[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), azetidine (0.2 ml) and ACN (3 ml ) Was prepared according to Example 25. MS m / z (relative intensity, 70 eV) 281 (M +, 3), 131 (6), 77 (5), 71 (5), 70 (bp).

Example 93

2-methyl-N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} propan-1-amine

[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), 2-methylpropan-1-amine (0.5 ml) and ACN (3 ml) to prepare according to Example 25. MS m / z (relative intensity, 70 eV) 297 (M +, 6), 254 (33), 130 (7), 87 (7), 86 (bp), 57 (9).

Example 94

1-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} pyrrolidine

[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), pyrrolidine (0.5 ml) and ACN ( 3 ml) was prepared according to Example 25. MS m / z (relative intensity, 70 eV) 295 (M +, 2), 131 (4), 85 (6), 84 (bp), 77 (3), 55 (4).

Example 95

1-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} piperidine

[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), piperidine (0.5 ml) and ACN ( 3 ml) was prepared according to Example 25. MS m / z (relative intensity, 70 eV) 309 (M +, 1), 131 (4), 99 (7), 98 (bp), 77 (3), 55 (5).

Example 96

3-fluoro-N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} propan-1-amine

3-fluoropropan-1-amine HCl-salt (0.178 g, 1.52 mmol) was basified on an SCX-3 ion exchange column (TEA / MeOH). [7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl 4-methylbenzenesulfonate (0.020 g, 0.0561 mmol) and 3-fluoropropan-1-amine ( MeOH / TEA: 0.15 M in 4/1, 5 ml) was heated at 120 ° C. under microwave irradiation for 1 h 20 min. MS m / z (relative intensity, 70 eV) 301 (M +, 3), 131 (8), 91 (9), 90 (bp), 86 (18), 70 (18).

Example 97

4-{[(S) -5-Fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} morpholine

[(2R) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.39 g, 0.95 mmol ), A mixture of morpholine (0.3 ml, 3.4 mmol) and ACN (3 ml) was heated at 120 ° C. under microwave irradiation for 70 minutes. Purification by SCX-3 column (TEA / MeOH) and flash column chromatography (isooctane / EtOAc / MeOH). Yield: 0.17 g. The amine was converted to hydrochloride and crystallized from MeOH / Et ₂ O. Mp 251 ° C. MS m / z (relative intensity, 70 eV) 331 (M +, 1), 207 (2), 101 (6), 100 (bp), 69 (2), 56 (5).

Example 98

N-({(2S) -7-[(trifluoromethyl) sulfonyl] -2,3-dihydro-1,4-benzodioxin-2-yl} methyl) propan-2-amine

{(2R) -7-[(trifluoromethyl) sulfonyl] -2,3-dihydro-1,4-benzodioxin-2-yl} methyl) 4-methylbenzenesulfonate (0.45 g, 1.0 mmol), propan-2-amine (1 ml) and ACN (2 ml) were heated at 120 ° C. for 20 minutes under microwave irradiation. The reaction mixture was purified by SCX-3 cation exchange column (MeOH / TEA) and flash chromatography (isooctane / EtOAc / MeOH). Yield: 0.150 g, 44%. The amine was converted to hydrochloride and crystallized from ACN. Mp 196.2-196.5 ° C. ESI MS m / z (relative intensity) 340 (M + 1, bp), 341 (16), 381 (14), 102 (8), 342 (6). [α] = − 62 ° (MeOH).

Production Example

Preparation Example 1

5-bromo-2- (oxirane-2-ylmethoxy) benzaldehyde

A mixture of 5-bromo-2-hydroxybenzaldehyde (10 g, 50 mmol), epibromohydrin (13.6 g, 100 mmol) and K ₂ CO ₃ (10.3 g, 75 mmol) in DMF (50 ml) was added at 60 ° C. Heated for hours. The mixture was cooled to ambient temperature and water and EtOAc were added. The phases were separated and the combined organic phases were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by flash column chromatography (isooctane / EtOAc) to afford the title compound (12.3 g). MS m / z (relative intensity, 70 eV) 256 (M +, 41), 201 (77), 200 (bp), 199 (84), 63 (60).

Production Example 2

5-bromo-2- (oxirane-2-ylmethoxy) phenyl formate

To a solution of 5-bromo-2- (oxirane-2-ylmethoxy) benzaldehyde (12.3 g, 47.7 mmol) in DCM (50 mL) was added m-CPBA (12.8 g, 57.2 mmol). The solution was heated to reflux for 3 hours 30 minutes and then brought to ambient temperature. Aqueous sodium bicarbonate (sat) and DCM were added and the phases were separated. The organic phase was washed with brine, dried (Na ₂ SO ₄ ), filtered and evaporated to dryness to afford the crude title compound. Crude yield: 12.3 g. MS m / z (relative intensity, 70 eV) 272 (M +, 7), 244 (50), 189 (95), 188 (bp), 57 (93).

Production Example 3

(7-bromo-2,3-dihydro-1,4-benzodioxin-2-yl) methanol

5-bromo-2- (oxirane-2-ylmethoxy) phenyl formate (12.6 g, 46.0 mmol) was dissolved in dioxane (50 ml) and KOH (10%) / NaOH (20%) was added. . Water and EtOAc were added and the phases were separated. The combined organic phases were washed with brine and dried to give the title compound (10.3 g). MS m / z (relative intensity, 70 eV) 245 (M +, 96) 244 (M +, bp), 213 (29), 189 (46), 188 (49).

Preparation Example 4

[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methanol

(7-Bromo-2,3-dihydro-1,4-benzodioxin-2-yl) methanol (0.5 g, 2.0 mmol), sodium methanesulfinate (85%) (0.37 g) in DMSO (4 ml) , 3.1 mmol), four batches of a mixture of CuI (0.039 g, 0.2 mmol), L-proline (0.047 g, 0.4 mmol) and K ₂ CO ₃ (0.056 g, 0.4 mmol) were purged with nitrogen at 140 ° C. for 1 hour. Heated under microwave irradiation in a flushed vial. The batch was mixed and diluted with water and HCl (1N). The resulting solution was extracted with EtOAc. The combined organic phases were washed with brine, dried and purified by flash column chromatography (isooctane / EtOAc / MeOH) to afford the title compound (0.89 g). MS m / z (relative intensity, 70 eV) 244 (M +, bp), 213 (40), 165 (27), 134 (22), 79 (18).

Preparation Example 5

[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate

[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methanol (0.9 g, 3.7 mmol), p-toluenesulfonyl chloride (1.0 in DCM) g, 5.5 mmol), TEA (0.76 ml, 5.5 mmol) and 4-DMAP (0.4 g, 3.7 mmol) were stirred at rt for 1 h 30 min. The solution was diluted with DCM and washed with HCl (1N), water and brine. The organic phase was dried and concentrated to give the title compound (1.1 g). MS m / z (relative intensity, 70 eV) 398 (M +, 51), 226 (bp), 225 (23), 213 (30), 91 (62).

Preparation Example 6

5-bromo-2-[(2S) -oxirane-2-ylmethoxy] benzaldehyde

5-bromo-2-hydroxybenzaldehyde (6 g, 30 mmol), (S) -glycidyl tosylate (8.2 g, 36 mmol), K ₂ CO ₃ (4.9 g, 36 mmol) and DMF (12 ml) Prepared according to Preparation Example 1. Water (100 ml) was added and the solution extracted with EtOAc (3 × 100 ml). The combined organic phases were washed with LiCl (5%, 100 ml), HCl (1N, 100 ml) and brine, dried and concentrated to give crude title compound (8.3 g). MS m / z (relative intensity, 70 eV) 257 (M +, 38), 256 (M +, 39), 200 (bp), 199 (87), 57 (88).

Preparation Example 7

5-bromo-2-[(2S) -oxirane-2-ylmethoxy] phenyl formate

Prepared using 5-bromo-2-[(2S) -oxirane-2-ylmethoxy] benzaldehyde (8.3 g, 32 mmol), DCM (100 ml) and m-CPBA (77%, 10.9 g, 48.6 mmol) Prepared according to Example 2. The mixture was heated to reflux for 3 hours. Crude yield: 8.5 g. MS m / z (relative intensity, 70 eV) 274 (M +, 10), 273 (M +, 9), 189 (98), 188 (bp), 57 (77).

Preparation Example 8

[(2R) -7-bromo-2,3-dihydro-1,4-benzodioxin-2-yl] methanol

5-Bromo-2-[(2S) -oxirane-2-ylmethoxy] phenyl formate (8.5 g, 31 mmol) was dissolved in dioxane. At 0 ° C. KOH (10%) was added. The mixture was stirred at rt for 1 h 30 and then concentrated. Water was added. Aqueous HCl (1N) was added to neutralize and then the solution was extracted with EtOAc (3x75ml). The combined organic phases were washed with brine, dried (Na ₂ SO ₄ ) and evaporated to dryness. Purification by flash column chromatography (isooctane / EtOAc) gave the crude title compound (4.4 g). MS m / z (relative intensity, 70 eV) 245 (M +, 97) 244 (M +, bp), 189 (48), 188 (50) 70 (39).

Preparation Example 9

[[(2R) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methanol

[(2R) -7-bromo-2,3-dihydro-1,4-benzodioxin-2-yl] methanol (2.2 g, 8.9 mmol) in DMSO (20 ml), sodium methanesulfinate (85% ) (1.6 g, 13.3 mmol), CuI (0.2 g, 0.9 mmol), L-proline (0.2 g, 1.8 mmol) and K ₂ CO ₃ (0.2 g, 1.8 mmol) were subjected to 3 hours at 140 ° C. Heated under microwave irradiation in a nitrogen-flushed vial. Water and EtOAc were added. The aqueous layer was extracted with EtOAc (3x100 ml) and the combined organic phases were washed with LiCl (5%), HCl (IN) and brine. The resulting solution was dried (Na ₂ SO ₄ ) and evaporated to dryness. The residue was purified by flash column chromatography (isooctane / EtOAc) to afford the title compound (1.7 g). MS m / z (relative intensity, 70 eV) 244 (M +, bp), 213 (39), 165 (26), 134 (22), 79 (23).

Preparation Example 10

[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate

[[(2R) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methanol (2.1 g, 8.6 mmol), p-toluenesulfonyl chloride (2.5 g, 12.8 mmol), TEA (1.8 ml, 12.8 mmol), 4-DMAP (1.0 g, 8.6 mmol) and DCM (anhydrous, 20 ml) were prepared according to Preparation Example 5. DCM (50 ml) was added and the solution was washed with HCl (100 ml, 1N), water (100 ml) and brine (100 ml) and evaporated to dryness to afford the title compound (3.0 g). MS m / z (relative intensity, 70 eV) 398 (M +, 49), 226 (bp), 225 (24), 213 (30), 91 (68).

Preparation Example 11

5-bromo-2-[(2R) -oxirane-2-ylmethoxy] benzaldehyde

5-bromo-2-hydroxybenzaldehyde (6 g, 29 mmol), (R) -glycidyltosylate (6.7 g, 29 mmol), K ₂ CO ₃ (4.9 g, 35 mmol) and DMF (12 ml) Prepared according to Preparation Example 1. The combined organic phases were washed with LiCl (5%, 100 ml), HCl (1N, 100 ml) and brine (100 ml) and evaporated to dryness. The residue was purified by flash column chromatography (isooctane / EtOAc) to afford crude title compound (6.8 g). MS m / z (relative intensity, 70 eV) 257 (M +, 38), 256 (M +, 39), 200 (bp), 199 (87), 57 (88).

Production Example 12

5-bromo-2-[(2R) -oxirane-2-ylmethoxy] phenyl formate

Prepared using 5-bromo-2-[(2R) -oxirane-2-ylmethoxy] benzaldehyde (6.8 g, 26 mmol), DCM (75 ml) and m-CPBA (77%, 8.9 g, 39.5 mmol) Prepared according to Example 2. Crude yield: 7.0 g. MS m / z (relative intensity, 70 eV) 274 (M +, 10), 273 (M +, 9), 189 (98), 188 (bp), 57 (77).

Preparation Example 13

[(2S) -7-bromo-2,3-dihydro-1,4-benzodioxin-2-yl] methanol

5-bromo-2-[(2R) -oxirane-2-ylmethoxy] phenyl formate (7.0 g, 25 mmol), dioxane (30 ml) and KOH (10%, 15 ml) were stirred for 1 hour. To prepare according to Preparation Example 8. Purification was performed by flash column chromatography (isooctane / EtOAc). Crude yield: 3.7 g. MS m / z (relative intensity, 70 eV) 245 (M +, 97) 244 (M +, bp), 189 (48), 188 (50) 79 (39).

Preparation Example 14

[[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methanol

[(2S) -7-bromo-2,3-dihydro-1,4-benzodioxin-2-yl] methanol (0.6 g, 2.3 mmol) in DMSO (3 ml), sodium methanesulfinate (85% ), A mixture of (0.4 g, 3.4 mmol), CuI (0.043 g, 0.2 mmol), L-proline (0.052 g, 0.5 mmol) and NaOH (0.018 g, 0.5 mmol) was added to nitrogen- at 140 ° C. for 2 hours 30 minutes. Heated under microwave irradiation in a flushed vial. The mixture was mixed with two different batches and water and EtOAc were added. The solution was extracted with EtOAc (3x50ml). The combined organic phases were washed with LiCl (5%), HCl (IN) and brine. The resulting solution was dried (Na ₂ SO ₄ ) and evaporated to dryness. Purification by flash column chromatography (isooctane / EtOAc) afforded the title compound (1.2 g). MS m / z (relative intensity, 70 eV) 244 (M +, bp), 213 (39), 165 (26), 134 (22), 79 (23).

Preparation Example 15

[(2R) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate

[[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methanol (1.2 g, 5.0 mmol), DCM (25 ml), p-toluene Prepared according to Preparation Example 10 using sulfonyl chloride (1.4 g, 7.5 mmol), TEA (1.0 ml, 12.8 mmol) and 4-DMAP (0.6 g, 5.0 mmol). Yield: 1.8 g. MS m / z (relative intensity, 70 eV) 398 (M +, 49), 226 (bp), 225 (24), 213 (30), 91 (68).

Production Example 16

4-bromo-2-fluorophenyl acetate

A mixture of 4-bromo-2-fluorophenol (5 g, 30 mmol) and acetic anhydride (13.4 g, 130 mmol) in pyridine (10.6 ml, 130 mmol) was heated at 100 ° C. for 3 hours and then brought to ambient temperature , Poured in water. HCl (IN and 6N) was added and the solution extracted with EtOAc. The combined organic phases were washed with sodium bicarbonate (saturated, 3 × 50 ml), dried (Na ₂ SO ₄ ) and evaporated to dryness to afford the title compound (5.8 g). MS m / z (relative intensity, 70 eV) 233 (M +, 11), 232 (M +, 12), 191 (95), 190 (bp), 161 (8).

Production Example 17

1- (5-Bromo-3-fluoro-7-hydroxyphenyl) ethanone

AlCl ₃ (5.0 g, 38 mmol) was added in portions to 4-bromo-2-fluorophenyl acetate (5.8 g, 25 mmol). The mixture was heated at 150 ° C. for 3 hours and then brought to ambient temperature. Water (ice-cooled) was added slowly followed by EtOAc. The resulting mixture was stirred vigorously, then the phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na ₂ SO ₄ ) and evaporated to dryness to afford the title compound (5.3 g). MS m / z (relative intensity, 70 eV) 233 (M +, 55), 232 (M +, 56), 218 (98), 217 (bp), 161 (10).

Preparation Example 18

1- [5-bromo-3-fluoro-2- (oxirane-2-ylmethoxy) phenyl] ethanone

1- (5-bromo-3-fluoro-2-hydroxyphenyl) ethanone (3.7 g, 15.8 mmol), epibromohydrin (2.6 ml, 31.7 mmol) and K ₂ CO in DMF (20 ml) A mixture of ₃ (3.3 g, 23.8 mmol) was heated at 60 ° C. for 1 h 50 min. The solution was brought to ambient temperature and water and EtOAc were added. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with LiCl (5%), HCl (1N) and brine, dried (Na ₂ SO ₄ ) and evaporated to dryness. Purification by flash column chromatography (isooctane / EtOAc) gave the title compound (3.9 g). MS m / z (relative intensity, 70 eV) 289 (M +, 13), 288 (M +, 14), 218 (91), 217 (bp), 81 (39), 57 (95).

Production Example 19

5-bromo-3-fluoro-2- (oxirane-2-ylmethoxy) phenyl acetate

1- [5-bromo-3-fluoro-2- (oxirane-2-ylmethoxy) phenyl] ethanone (1.3 g, 4.5 mmol) and m-CPBA (4.0 g, 18 mmol) in DCM (25 ml) The solution of was heated to reflux. After 22 hours, additional m-CPBA (2.7 g, 12 mmol) was added and the mixture was heated to reflux for an additional 22 hours and then brought to ambient temperature. The solid was filtered off and washed. The filtrate obtained was washed with sodium bicarbonate (sat) and brine, dried (Na ₂ SO ₄ ) and evaporated to dryness to afford the crude title compound (2.6 g). MS m / z (relative intensity, 70 eV) 305 (M +, 5), 304 (M +, 6), 263 (97), 262 (bp), 206 (49), 57 (65).

Production example 20

(7-bromo-5-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl) methanol

5-Bromo-3-fluoro-2- (oxirane-2-ylmethoxy) phenyl acetate (2.6 g, 8.7 mmol) was stirred in dioxane at room temperature. Aqueous KOH (10%) was added until basic pH was reached (1: 1 water / KOH (10%)). Water was added and the solution extracted with EtOAc. The combined organic phases were washed with brine, dried and evaporated to dryness to afford the title compound (0.8 g). MS m / z (relative intensity, 70 eV) 263 (M +, 97), 262 (M +, bp), 218 (39), 207 (50), 206 (51).

Production Example 21

[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methanol

(7-Bromo-5-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl) methanol (0.6 g, 2.3 mmol) in DMSO (6 ml), sodium methanesulfinate (85 %) (0.4 g, 3.5 mmol), CuI (0.04 g, 0.2 mmol), a mixture of L-proline (0.05 g, 0.5 mmol) and K ₂ CO ₃ (0.06 g, 0.5 mmol) in 140 ° C. in two batches Heated under microwave irradiation in a nitrogen-fluxed vial for 2 hours. After cooling to ambient temperature, the batches were mixed, water and EtOAc were added and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with LiCl (5%), HCl (1N) and brine, dried (Na ₂ SO ₄ ) and evaporated to dryness. The product was also mixed with another batch of the same compound. Purification by flash column chromatography (isooctane / EtOAc / MeOH) afforded the title compound (0.2 g). MS m / z (relative intensity, 70 eV) 262 (M +, bp), 231 (32), 206 (12), 183 (17), 152 (14).

Production Example 22

[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate

[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methanol (0.4 g, 1.7 mmol) in DCM (10 ml), toluenesulfonyl A solution of chloride (0.5 g, 2.6 mmol), TEA (0.4 ml, 2.6 mmol) and 4-DMAP (0.2 g, 1.7 mmol) was stirred at room temperature for 1 hour. DCM was added and the resulting mixture was washed with HCl (IN) and brine. The organic phase was dried (Na ₂ SO ₄ ) and evaporated to dryness to afford the title compound (0.7 g). MS m / z (relative intensity, 70 eV) 416 (M +, 31), 244 (bp), 243 (26), 231 (19), 91 (70).

Preparation Example 23

1- (5-Bromo-3-fluoro-2-[(2R) -oxirane-2-ylmethoxy] phenyl) ethanone

1- (5-Bromo-3-fluoro-2-hydroxyphenyl) ethanone (16.8 g, 72 mmol), (R) -glycidyl tosylate (18.1 g, 79 mmol), K ₂ CO ₃ (15.0 g, 108 mmol) and DMF (60 ml) were prepared according to Preparation Example 1. The combined organic phases were washed with LiCl (5%), HCl (IN). Purification by flash column chromatography (isooctane / EtOAc) gave the title compound (8.3 g). MS m / z (relative intensity, 70 eV) 290 (M +, 9), 288 (M +, 9), 217 (bp), 81 (47), 57 (46).

Preparation Example 24

5-bromo-3-fluoro-2-[(2R) -oxirane-2-ylmethoxy] phenyl acetate

1- (5-Bromo-3-fluoro-2-[(2R) -oxirane-2-ylmethoxyphenyl) ethanone (19.5 g, 67 mmol), CHCl ₃ and m-CPBA (77%, 60.5 g) , 27 mmol) was prepared according to Preparation Example 7. The mixture was heated to reflux for 24 hours. The crude product was further used (Preparation 25). MS m / z (relative intensity, 70 eV) 306 (M +, 4), 304 (M +, 4) 262 (bp), 69 (69), 57 (99).

Preparation Example 25

[(2S) -7-bromo-5-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl] methanol

1- (5-Bromo-3-fluoro-2-[(2R) -oxirane-2-ylmethoxy] phenyl acetate (crude, up to 67 mmol) was stirred in dioxane at 0 ° C. NaOH (15 %) Was added until the mixture reached pH 14. The mixture was stirred for 30 minutes at room temperature and then concentrated, water was added and the mixture was extracted with EtOAc The combined organic phases were washed with brine, Dry (Na ₂ SO ₄ ) and evaporated to dryness to afford crude title compound: yield: 10.3 g MS m / z (relative intensity, 70 eV) 262 (M +, bp), 264 (M +, bp), 206 70, 81 (58), 69 (55), 57 (53).

Preparation Example 26

[(2S) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methanol

[(2S) -7-bromo-5-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl] methanol (2.35 g, 8.9 mmol) in DMSO (6 ml), sodium methane Prepared according to Preparation Example 21 using sulfinate (85%) (1.29 g, 107 mmol), CuI (0.34 g, 1.8 mmol), L-proline (0.41 g, 3.6 mmol) and NaOH (0.071 g, 1.8 mmol). It was. Yield 0.98 g. MS m / z (relative intensity, 70 eV) 262 (M +, bp), 231 (35), 183 (22), 152 (23), 57 (30).

Preparation Example 27

[(2R) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl4-methylbenzenesulfonate

[[(2S) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methanol (0.97 g, 3.7 mmol), DCM (20 ml ), p-toluenesulfonyl chloride (1.06 g, 5.6 mmol), TEA (0.78 ml, 5.6 mmol) and 4-DMAP (0.46 g, 3.7 mmol) were prepared according to Preparation Example 10. Yield: 1.47 g. MS m / z (relative intensity, 70 eV) 416 (M +, 40), 244 (bp), 243 (26), 231 (19), 91 (50).

Preparation Example 28

4-[(trifluoromethyl) sulfonyl] phenol

A mixture of 4-[(trifluoromethyl) thio] phenol (4.5 g, 23.2 mmol), Na ₂ WO ₄ .2H ₂ O (0.08 g, 0.24 mmol) and hydrogen peroxide (6 ml, 59 mmol) in acetic acid (25 ml) Heated at 65 ° C. overnight. Na ₂ S ₂ O ₅ (saturated) and NaOH (20%) were added (until pH 8) and the solution extracted with EtOAc. The combined organic phases were dried (Na ₂ SO ₄ ) and evaporated to dryness to afford crude title compound (6.0 g). MS m / z (relative intensity, 70 eV) 226 (M +, 18), 157 (bp), 109 (14), 93 (52), 65 (53).

Preparation Example 29

4-[(trifluoromethyl) sulfonyl] phenyl acetate

Prepared according to Preparation 16 using 4-[(trifluoromethyl) sulfonyl] phenol (4.5 g, 23.2 mmol), acetic anhydride (13.4 g, 130 mmol) and pyridine (10.6 ml, 130 mmol). Crude yield: 6.8 g. MS m / z (relative intensity, 70 eV) 268 (M +, 6), 157 (bp), 93 (84), 65 (52), 64 (43).

Preparation Example 30

1- {2-hydroxy-5-[(trifluoromethyl) sulfonyl] phenyl} ethanone

Prepared according to Preparation 17 using AlCl ₃ (4.66 g, 35 mmol) and 4-[(trifluoromethyl) sulfonyl] phenyl acetate (6.8 g, 23.2 mmol). Yield 3.2 g. MS m / z (relative intensity, 70 eV) 268 (M +, 37), 253 (32), 199 (bp), 120 (29), 107 (22).

Preparation Example 31

1- {2-[(2R) -oxirane-2-ylmethoxy] -5-[(trifluoromethyl) sulfonyl] phenyl} ethanone

1- {2-hydroxy-5-[(trifluoromethyl) sulfonyl] phenyl} ethanone (3.2 g, 11.9 mmol), (R) -glycidyltosylate (3.2 g, 14 mmol), K ₂ Prepared according to Preparation 23 using CO ₃ (2.0 g, 14.3 mmol) and DMF (30 ml). Yield 2.2 g. MS m / z (relative intensity, 70 eV) 324 (M +, 4), 277 (83), 255 (69), 253 (67), 199 (bp).

Preparation Example 32

2-[(2R) -oxirane-2-ylmethoxy] -5-[(trifluoromethyl) sulfonyl] phenyl acetate

1- {2-[(2R) -oxirane-2-ylmethoxy] -5-[(trifluoromethyl) sulfonyl] phenyl} ethanone (1.2 g, 3.7 mmol) and m in CHCl ₃ (50 ml) Prepared according to Preparation Example 19, using CPBA (4.95 g, 22.5 mmol). Crude yield 1.0 g. MS m / z (relative intensity, 70 eV) 298 (34), 229 (77), 165 (bp), 107 (39), 79 (30).

Preparation Example 33

[(2S) -7- (trifluoromethylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methanol

2-[(2R) -oxirane-2-ylmethoxy] -5-[(trifluoromethyl) sulfonyl] phenyl acetate (1.0 g, 3.7 mmol), dioxane (10 ml) and KOH (10%, 10 ml ) Was prepared according to Preparation 20, and the mixture was stirred at room temperature for 1 hour. Yield 1.0 g. MS m / z (relative intensity, 70 eV) 298 (M +, 29), 229 (72), 165 (bp), 107 (67), 79 (33).

Preparation Example 34

[(2R) -7- (trifluoromethylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate

[7- (trifluoromethylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methanol (0.75 g, 2.5 mmol) in DCM (40 ml) stirred for 18 hours, Prepared according to Preparation Example 22 using toluenesulfonyl chloride (0.72 g, 3.8 mmol), TEA (0.42 ml, 3 mmol) and 4-DMAP (0.37 g, 3.0 mmol). Yield 0.28 g. MS m / z (relative intensity, 70 eV) 452 (M +, bp), 383 (41), 280 (82), 211 (80), 91 (84).

Preparation 35

2- (benzyloxy) -1-chloro-3-fluorobenzene

A mixture of 2-chloro-6-fluorophenol (25 g, 170 mmol), acetone (200 ml), K ₂ CO ₃ (47.08 g, 340 mmol) and benzylbromide (22.31 ml, 187 mmol) was heated at 65 ° C. for 16 hours. . The solution was filtered and evaporated. Water (100 ml) was added and the solution extracted with EtOAc. The combined organic phases were dried (Na ₂ SO ₄ ) and evaporated to dryness to give the title compound (32.3 g). MS m / z (relative intensity, 70 eV) 236 (M +, 2), 117 (4), 92 (8), 91 (bp), 65 (13).

Preparation Example 36

2- (benzyloxy) -3-fluorophenol

2- (benzyloxy) -1-chloro-3-fluorobenzene (3 g, 12.71 mmol), dioxane (6 ml), KOH (0.78 g, 14 mmol), water (6 ml), tris (dibenzylideneacetone) di A mixture of palladium (0.12 g, 0.13 mmol) and 2-di-tert-butylphosphine-2,4,6-triisopropylbiphenyl (0.22 g, 0.51 mmol) was flushed with N ₂ and at 120 ° C Heated under microwave irradiation for 7 minutes. HCl (1N) was added and the solution was extracted with EtOAc. The combined organic phases were dried (Na ₂ SO ₄ ) and evaporated to dryness. Purification by flash column chromatography (isooctane / EtOAc) afforded the title compound (1.86 g). MS m / z (relative intensity, 70 eV) 218 (M +, 4), 92 (8), 91 (bp), 65 (13), 51 (9).

Preparation Example 37

2-{[2- (benzyloxy) -3-fluorophenoxy] methyl} oxirane

2- (benzyloxy) -3-fluorophenol (8.9 g, 40.8 mmol), K ₂ CO ₃ (11.3 g, 81.6 mmol), (R) -glycidyl tosylate (16 g, stirred at 60 ° C. for 16 hours) 10.2 g, 44.9 mmol) and DMF (50 ml) were prepared according to Preparation 23. Yield 9.15 g. MS m / z (relative intensity, 70 eV) 274 (M +, 6), 153 (5), 92 (8), 91 (bp), 65 (10).

Preparation Example 38

2-fluoro-6- (oxirane-2-ylmethoxy) phenol

Triethyl under N _{2 in} a mixture of 2-{[2- (benzyloxy) -3-fluorophenoxy] methyl} oxirane (8 g, 29.2 mmol), ethanol (65 ml) and Pd / C (0,5 g) Silane (9.3 ml, 58.2 mmol) was added dropwise. The solution was stirred for 16 h at room temperature and filtered through celite. The solvent was evaporated and Na ₂ CO ₃ (10%) was added and the solution extracted with EtOAc. The combined organic phases were dried (Na ₂ SO ₄ ) and evaporated to dryness. Flash column chromatography (isooctane / EtOAc) gave the title compound (3.5 g). MS m / z (relative intensity, 70 eV) 184 (M +, bp), 153 (44), 139 (31), 128 (99), 57 (23).

Preparation Example 39

[(2S) -8-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl] methanol

Prepared according to Production Example 20 using 2-fluoro-6- (oxirane-2-ylmethoxy) phenol (3.9 g, 21.2 mmol), dioxane (20 ml) and KOH (10%, 10 ml). The mixture was stirred at rt for 1.5 h. Yield 3.8 g. MS m / z (relative intensity, 70 eV) 338 (50), 166 (bp), 165 (42), 139 (24), 91 (51).

Preparation Example 40

[(2R) -8-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate

[(2S) -8-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl] methanol (7.05 g, 38.0 mmol), toluenesulphur in DCM (75 ml) stirred for 1.5 h Prepared according to Preparation Example 22 using polyvinyl chloride (10.9 g, 57 mmol), TEA (8.0 ml, 57 mmol) and 4-DMAP (4.7 g, 38.0 mmol). Flash column chromatography gave 11.9 g of the title compound. MS m / z (relative intensity, 70 eV) 184 (90), 153 (43), 139 (29), 128 (bp), 57 (25).

Preparation Example 41

N-{[(2S) -8-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine

[(2R) -8-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (4.0 g, 11.8 mmol), ethanamine (5 ml, water 70%) and ACN (10 ml) were prepared according to Preparation Example 5. Flash column chromatography (isooctane / EtOAc / MeOH) gave 2.0 g of the title compound. MS m / z (relative intensity, 70 eV) 211 (M +, 17), 70 (10), 59 (4), 58 (bp), 56 (4).

Preparation Example 42

N-benzyl-N-{[(2S) -8-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine

N-{[(2S) -8-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine (1.95 g, 9.2 mmol), K ₂ CO ₃ (2.55 g, 18.5 mmol), benzylbromide (1.3 ml, 11.1 mmol), a NaI spatula (<5 mg) and acetonitrile were heated at 120 ° C. under microwave irradiation for 20 minutes. The solution is filtered, evaporated, Na ₂ CO ₃ (10%) is added and the solution is extracted with EtOAc. The combined organic phases were dried (Na ₂ SO ₄ ) and evaporated to dryness. Purification on flash column chromatography (isooctane / EtOAc) afforded 2.3 g of the title compound. MS m / z (relative intensity, 70 eV) 149 (10), 148 (86), 92 (8), 91 (bp), 65 (7).

Preparation Example 43

N-benzyl-N-{[(2S) -8-fluoro-7- (methylthio) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine

N-benzyl-N-{[(2S) -8-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine (2.2 g, 7.3 mmol) and 2, A mixture of 2-tetramethylpiperidine (2.5 ml, 14.6 mmol) was added to n-BuLi (10 ml, 25 mmol) in THF (anhydrous, 10 ml) at −75 ° C. under N ₂ and then THF (anhydrous, 10 ml) Dimethyl sulfide (1.32 ml, 14.6 mmol) was added. The mixture was stirred for 30 min at -75 ° C and then warmed to room temperature. NH ₄ Cl (sat) was added and the solution was extracted with EtOAc. The combined organic phases were washed with Na ₂ SO ₃ (15%) and brine, dried (Na ₂ SO ₄ ) and evaporated to dryness. Flash column chromatography (isooctane / EtOAc) gave the title compound (1.3 g). MS m / z (relative intensity, 70 eV) 347 (2), 149 (12), 148 (100), 92 (7), 91 (92).

Preparation Example 44

N-benzyl-N-{[(2S) -8-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine

N-benzyl-N-{[(2S) -8-fluoro-7- (methylthio) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} in acetic acid (10 ml) Ethaneamine (1.2 g, 3.5 mmol), Na ₂ WO ₄ ㆍ 2H ₂ O (0.01 g, 0.035 mmol) and hydrogen peroxide (0.9 ml, 8.6 mmol) were heated at 50 ° C. for 2 hours according to Preparation Example 28. Prepared. The product was purified by flash column chromatography (isooctane / EtOAc) to afford the title compound (1.0 g). MS m / z (relative intensity, 70 eV) 149 (11), 148 (bp), 92 (6), 91 (72), 65 (4).

Preparation Example 45

N-{[(2S) -8-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-propan-1-amine

[(2R) -8-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (4.0 g, 11.8 mmol), ethanamine (5 ml, water 70%) and ACN (10 ml) were prepared according to Example 5. Flash column chromatography (isooctane / EtOAc) gave the title compound (2.35 g). MS m / z (relative intensity, 70 eV) 225 (M +, 25), 98 (8), 73 (5), 72 (bp), 70 (13).

Preparation Example 46

N-benzyl-N-{[(2S) -8-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-propan-1-amine

N-{[(2S) -8-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-propan-1-amine (2.3 g, 10.2 mmol), Prepared according to Preparation Example 42 using K ₂ CO ₃ (2.82 g, 18.5 mmol), benzylbromide (1.3 ml, 11.1 mmol), a spatula NaI and acetonitrile (10 ml). Yield 2.2 g. MS m / z (relative intensity, 70 eV) 163 (10), 162 (77), 92 (8), 91 (bp), 65 (7).

Preparation Example 47

N-benzyl-N-{[(2S) -8-fluoro-7- (methylthio) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-propane- 1-amine

N-benzyl-N-{[(2S) -8-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-propan-1-amine (2.2 g, 7.0 mmol), 2,2-tetramethylpiperidine (3.5 ml, 21 mmol), n-BuLi (9.5 ml, 23.8 mmol), dimethylsulfide (1.25 ml, 14 mmol) and THF (anhydrous, 20 ml) Prepared according to Example 43. Flash column chromatography (isooctane / EtOAc) gave the title compound (0.8 g). MS m / z (relative intensity, 70 eV) 361 (3), 163 (12), 162 (bp), 92 (5), 91 (60).

Preparation Example 48

N-benzyl-N-{[(2S) -8-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-propane -1-amine

N-benzyl-N-{[(2S) -8-fluoro-7- (methylthio) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-propane- Prepared according to Preparation Example 44 using 1-amine (0.78 g, 2.15 mmol), Na ₂ WO ₄ .2H ₂ O (0.007 g, 0.025 mmol), hydrogen peroxide (0.55 ml, 5.5 mmol) and acetic acid (10 ml). . Yield 0.36 g. MS m / z (relative intensity, 70 eV) 163 (13), 162 (bp), 92 (7), 91 (88), 65 (5).

Preparation 49

4-bromo-2-chlorophenyl acetate

Prepared according to Preparation 16 using 4-bromo-2-chlorophenol (6 g, 29 mmol) and acetic anhydride (13.4 g, 130 mmol) in pyridine (10.5 ml, 130 mmol). Yield 7.4 g. MS m / z (relative intensity, 70 eV) 210 (25), 208 (bp), 206 (79), 63 (21), 62 (9), 250 (M +, 8).

Preparation 50

1- (5-Bromo-3-chloro-hydroxyphenyl) ethanone

Prepared according to Preparation 17 using AlCl ₃ (4.7 g, 36 mmol) and 4-bromo-2-chlorophenyl acetate (5.9 g, 24 mmol). Yield 5.5 g. MS m / z (relative intensity, 70 eV) 250 (M +, 41), 248 (M +, 31), 235 (bp), 233 (79), 62 (26).

Preparation Example 51

1- [5-bromo-3-chloro-2- (oxirane-2-ylmethoxy) phenyl] ethanone

1- (5-Bromo-3-chloro-2-hydroxyphenyl) ethanone (5.5 g, 21.9 mmol), (2R)-(-) glycidyl tosylate (10 g, 43.8 mmol) in DMF (25 ml) ) And K ₂ CO ₃ (4.5 g, 32.9 mmol) were heated at 60 ° C. for 25 h. The solution was brought to ambient temperature and water and EtOAc were added. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with LiCl (5%), HCl (1N) and brine, then dried (Na ₂ SO ₄ ) and evaporated to dryness. Purification by flash column chromatography (isooctane / EtOAc) afforded the title compound (5.0 g). MS m / z (relative intensity, 70 eV) 250 (30), 248 (M +, 26), 235 (bp), 233 (85), 57 (90), 306 (M +, 9).

Preparation Example 52

5-bromo-3-chloro-2- (oxirane-2-ylmethoxy) phenyl acetate

Of 1- [5-bromo-3-chloro-2- (oxirane-2-ylmethoxy) phenyl] ethanone (1.7 g, 5.6 mmol) and m-CPBA (2.4 g, 14 mmol) in DCM (30 ml) The solution was heated to 50 ° C. After 22 hours, additional m-CPBA (2.4 g, 14 mmol) was added and the mixture was heated to 50 ° C. for an additional 44 hours and then brought to ambient temperature. The solid was filtered off and washed. The filtrate obtained was washed with sodium bicarbonate (sat) and brine, further dried (Na ₂ SO ₄ ) and evaporated off to afford the crude title compound (2.7 g). MS m / z (relative intensity, 70 eV) 280 (bp), 278 (84), 224 (54), 222 (52), 57 (79), 322 (M +, 5).

Preparation Example 53

(7-bromo-5-chloro-2,3-dihydro-1,4-benzodioxin-2-yl) methanol

To a solution of 5-bromo-3-chloro-2- (oxirane-2-ylmethoxy) phenyl acetate (4.4 g, 13.7 mmol) in dioxane (20 ml) was added KOH (10%, 40 ml) at 0 ° C. It was. The reaction mixture was stirred at rt for 2 h. Water was added and the solution extracted with EtOAc. The combined organic phases were washed with brine, dried (Na ₂ SO ₄ ) and evaporated to dryness. Purification by flash column chromatography (isooctane / EtOAc) gave the title compound (0.34 g). MS m / z (relative intensity, 70 eV) 280 (M +, bp), 278 (78), 224 (68), 222 (54), 57 (37).

Preparation Example 54

[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methanol

(7-Bromo-5-chloro-2,3-dihydro-1,4-benzodioxin-2-yl) methanol (1.07 g, 3.8 mmol) in DMSO (10 ml), sodium methanesulfinate (85% ) (0.6 g, 5.7 mmol), CuI (0.07 g, 0.4 mmol), L-proline (0.09 g, 0.8 mmol) and K ₂ CO ₃ (0.04 g, 0.8 mmol) were prepared according to Preparation Example 9. . Yield (0.33 g). MS m / z (relative intensity, 70 eV) 280 (38), 278 (M +, bp), 247 (35), 207 (18), 57 (18).

Preparation Example 55

[(2R) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate

[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methanol (0.33 g, 1.2 mmol), DCM (10 ml), Prepared according to Preparation 22 using p-toluenesulfonyl chloride (0.34 g, 1.8 mmol), TEA (0.18 ml, 1.8 mmol) and 4-DMAP (0.15 g, 1.2 mmol). Yield: 0.47 g. MS m / z (relative intensity, 70 eV) 344 (28), 342 (bp), 340 (74), 263 (18), 233 (31). However, molecular ions did not show fragmentation consistent with the title compound. It was used directly in the following examples (Example 38) without further analysis.

Preparation Example 56

1- [2-methoxy-4- (methylthio) phenyl] ethanone

Sodium thiomethoxide (1.3 g, 18.5 mmol) in DMF (15 ml) was added to 1- (4-fluoro-2-methoxyphenyl) ethanone (2.85 g, 16.9 mmol) in DMF (5 ml). The mixture was stirred overnight at room temperature. HCl (1%) was added, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with LiCl (5%) and brine and concentrated to give the title compound (3.6 g). MS m / z (relative intensity, 70 eV) 196 (M &lt; + &gt;, 35), 182 (11), 181 (bp), 166 (8), 136 (10).

Preparation Example 57

1- [2-hydroxy-4- (methylthio) phenyl] ethanone

Boron tribromide (19 ml, 1N in DCM, 19 mmol) was added to a mixture of crude 1- [2-methoxy-4- (methylthio) phenyl] ethanone (3.6 g, 16.9 mmol) and DCM (25 ml) at 0 ° C. Added. The mixture was brought to room temperature and stirred for 3 hours. Ice / water was added, the organic phase was separated and the aqueous phase extracted with EtOAc. The combined organic phases were filtered through a short plug of silica (EtOAc) and concentrated to give the title compound (3.0 g). MS m / z (relative intensity, 70 eV) 183 (6), 182 (M +, 53), 168 (10), 167 (bp), 152 (6).

Preparation 58

1- [2-hydroxy-4- (methylsulfonyl) phenyl] ethanone

1- [2-hydroxy-4- (methylthio) phenyl] ethanone (3.0 g, 16.6 mmol) in acetic acid (15 ml) heated to 60 ° C. overnight, Na ₂ WO ₄ -2H ₂ O (0.056 g, 0.17 mmol) and hydrogen peroxide (4.2 ml, 41.3 mmol) according to Preparation 28. Yield: 3.0 g. MS m / z (relative intensity, 70 eV) 214 (M +, 18), 200 (12), 199 (bp), 137 (47), 120 (13).

Preparation Example 59

7- (methylsulfonyl) -4-oxo-4H-chromen-2-carboxylate

A solution of sodium (1.87 g, 81.5 mmol) in EtOH (70 ml) was added 1- [2-hydroxy-4- (methylsulfonyl) phenyl] ethanone (3.52 g, 16.3 mmol), diethyl oxalate (7.14 g). , 48.9 mmol) and EtOH (40 ml). The mixture was heated to reflux for 2 hours. The mixture was cooled to ambient temperature and HCl (concentrated), EtOAc and HCl (10%) were added. The phases were separated and the combined organic phases were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. Purification by flash chromatography (EtOAc / isooctane / MeOH) afforded the title compound. Yield 5.5 g. MS m / z (relative intensity, 70 eV) 297 (15), 296 (M +, bp), 268 (27), 217 (60), 189 (19).

Preparation Example 60

Ethyl 7- (methylsulfonyl) chroman-2-carboxylate

Ethyl 7- (methylsulfonyl) -4-oxo-4H-chromen-2-carboxylate (1.3 g, 4.4 mmol), palladium on carbon (10%, 0.44 g), MeOH (45 ml) and AcOH (5 ml) The mixture of was hydrogenated to 60 ° C. at 40 Psi for 64 hours. Filtration through Celite (EtOAc) and evaporation followed by filtration through a plug of Al ₂ O ₃ (EtOAc / ACN) gave the title compound. Yield: 0.6 g. MS m / z (relative intensity, 70 eV) 307 (64), 302 (91), 286 (14), 285 (M + 1, bp), 211 (18).

Preparation Example 61

[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methanol

A mixture of ethyl 7- (methylsulfonyl) chroman-2carboxylate (0.6 g, 2.1 mmol), LiBH ₄ (0.18 g, 8.5 mmol) and THF (8 ml) was added at 2 ° C. for 15 minutes and at room temperature. Stir for hours. HCl (10%) and EtOAc were added and the organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound. Yield 0.66 g. MS m / z (relative intensity, 70 eV) 507 (20), 485 (25), 265 (23), 244 (13), 243 (M + 1, bp).

Preparation Example 62

[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl 4-methylbenzenesulfonate

[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methanol (0.4 g, 1.65 mmol), DCM (25 ml), p-toluenesulfonyl chloride, stirred at room temperature overnight (0.47 g, 2.5 mmol), TEA (0.28 ml, 2.0 mmol) and 4-DMAP (0.24 g, 2.0 mmol) were prepared according to Preparation 22. Yield: 0.59 g. MS m / z (relative intensity, 70 eV) 419 (62), 416 (14), 415 (25), 414 (bp), 397 (M + 1, 39).

Preparation Example 63

[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methylamine

[(2R) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (1.1 g, 2.5 mmol), NH ₃ ( 4 ml, 7N in methanol) were heated at 120 ° C. for 20 minutes under microwave irradiation. The product was evaporated to dryness and purified by flash column chromatography (EtOAc / MeOH). Yield 0.31 g. MS m / z (relative strength, 70 eV) 243 (M +, 35), 214 (bp), 199 (35), 79 (25), 56 (22).

Preparation Example 64

[(2S) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methylamine

[(2R) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl 4-methylbenzenesulfonate (0.7 g, 1.7 mmol ), NH ₃ (6 ml, 7N in methanol) was heated at 120 ° C. under microwave irradiation for 20 minutes. The product was evaporated to dryness and purified on an SCX-3 column (TEA / MeOH). Yield 0.34 g. MS m / z (relative intensity, 70 eV) 261 (M +, bp), 217 (49), 97 (39), 69 (55), 56 (79).

Preparation 65

Ethyl 7-hydroxychroman-2-carboxylate

A mixture of ethyl 7-hydroxy-4-oxo-4H-chromen-2-carboxylate (10 g, 41 mmol) in MeOH (20 ml) and AcOH (20 ml) was hydrogenated at 50 Psi for 4 days. Filtration and evaporation gave the title compound. Yield: 9.2 g. MS m / z (relative intensity, 70 eV) 222 (M +, 44), 149 (bp), 148 (22), 147 (46), 121 (25).

Preparation 66

Ethyl 7-([(trifluoromethyl) sulfonyl] oxy} chroman-2-carboxylate

A mixture of ethyl 7-hydroxychroman-2-carboxylate (9.8 g, 44 mmol) in CH ₂ Cl ₂ (150 ml) was cooled to 0 ° C., pyridine (6.97 g, 88 mmol) was added and trifluoromethane Sulfonic anhydride (8.9 ml, 53 mmol) was added in portions for 40 minutes, then brought to ambient temperature and stirred for 2 hours. HCl (aq, 10%) was added and the solution was extracted with CH ₂ Cl ₂ . Wash the combined organic phases with _{Na 2 CO 3 (H 2 O} 10% of) and Na ₂ CO ₃ (sat.), Dried (Na ₂ SO ₄₎ and evaporated to dryness to give the crude title compound (13.2g) . MS m / z (relative intensity, 70 eV) 354 (M &lt; + &gt;, 41), 281 (bp), 280 (16), 147 (42), 103 (19).

Preparation Example 67

Ethyl 7-[(triisopropylsilyl) thio] chroman-2-carboxylate

Triisopropylsilanethiol (4.24 g, 22.3 mmol) was added to a suspension of NaH (1.02 g, 25.6 mmol, 60% in mineral oil) in toluene (60 ml). After stirring for 30 minutes at room temperature, the mixture was added to ethyl 7-{[(trifluoromethyl) sulfonyl] oxy} chroman-2-carboxylate (6.07 g, 17.1 mmol) and tetrakis in THF (60 ml). A solution of (triphenylphosphine) palladium (0.39 g, 0.34 mmol) was added and the mixture was degassed under N ₂ . After heating at 90 ° C. under N ₂ for 1.5 h, the solvent was evaporated and the residue was purified by column chromatography (EtOAc / isooctane) to afford the title compound. Yield: 6.84 g. MS m / z (relative intensity, 70 eV) 394 (M +, 27), 277 (52), 352 (26), 351 (bp), 251 (50).

Preparation Example 68

Ethyl 7-mercaptochroman-2carboxylate

To a mixture of ethyl 7-[(triisopropylsilyl) thio] chroman-2-carboxylate (5.6 g, 14.2 mmol) in EtOH (100 ml) was added concentrated HCl (4 ml) and the mixture was stirred at room temperature for 3 hours. Stirred. Evaporation to dryness afforded the title compound. Yield: 3.4 g. MS m / z (relative intensity, 70 eV) 238 (M +, 75), 165 (bp), 163 (56), 132 (50), 131 (43).

Preparation Example 69

Ethyl 7- (methylthio) chroman-2-carboxylate

A mixture of ethyl 7-mercaptochroman-2 carboxylate (3.4 g, 14.3 mmol), methyl iodide (3.03 g, 21.4 mmol) and K ₂ CO ₃ (7.88 g, 57 mmol) in ACN (100 ml) was prepared. Stir at room temperature for hours. Filtration and evaporation of the solvent gave the title compound (3.28 g). MS m / z (relative intensity, 70 eV) 252 (M +, bp), 179 (94), 177 (40), 132 (55), 131 (63).

Preparation Example 70

Ethyl 7- (methylsulfonyl) chroman-2-carboxylate

Ethyl 7- (methylthio) chroman-2-carboxylate (3.28 g, 13.0 mmol) in acetic acid (40 ml), Na ₂ WO ₄ 2H ₂ O (0.04 g, 0.13 mmol) and hydrogen peroxide (3.3 ml, 32.5 mmol ) Was heated at 60 ° C. for 1 h. Na ₂ S ₂ O ₅ (5%, 150 ml) was added and the solution was extracted with EtOAc. The combined organic phases were washed with Na ₂ CO ₃ (10%), dried (MgSO ₄ ) and evaporated to dryness to afford crude title compound (2.44 g). MS m / z (relative intensity, 70 eV) 284 (M +, 37), 211 (bp), 149 (27), 132 (54), 131 (55).

Biological activity

The following test is used for the evaluation of the compounds according to the invention.

In Vivo Testing: Behavior

Behavioral activation is available on 8 Digiscan Active Monitors (RXYZM (16) TAO, Omnitech Electronics, Columbus, OH, USA) connected to the Omnitech Disiscan analyer and Digital Interface Board (NB DIO-24, National Instruments, Measurements can be made using an Apple Macintosh computer equipped with USA). Each active monitor consists of a secondary metal frame (W x L = 40 cm x 40 cm) with a photobeam sensor. While measuring behavioral activity, rats were placed in a clear acrylic cage (W × L × H, 40 × 40 × 30 cm) and then placed back into the activity monitor. Each active monitor has three rows of infrared photobeam sensors, each row consisting of 16 sensors. Two rows are placed at 90 ° angles along the front and sides of the cage bottom, and the third row is placed 10 cm above the floor to measure vertical activity. The photobeam sensors are spaced 2.5 cm apart. Each active monitor is fixed to the same sound and light attenuation box containing weak house light and fan.

Computer software is recorded using object orientation programming (LabVIEW®, National instruments, Austin, TX, USA).

Behavioral data from each activity monitor indicating the animal's position (horizontal center of gravity and vertical activity) at each time was recorded at a sampling frequency of 25 Hz and collected using a commonly recorded LABView ™ application. Data from each recording session was stored and analyzed for distance traveled. Each behavior recording session begins approximately 4 minutes after injection of the test compound and lasts 60 minutes. Similar behavior recording processes apply to drug-naive and drug pretreatment rats. Rats pretreated with d-amphetamine provide an intraperitoneal dose of 1.5 mg / kg 10 minutes prior to the recording session on an activity monitor. Rats pretreated with MK-801 provide an intraperitoneal dose of 0.7 mg / kg 90 minutes prior to the recording session on an activity monitor. Results are expressed in coefficients / 60 minutes or coefficients / 30 minutes as arbitrary length units. Statistical comparisons are performed using Student's t-test on the control group. In MK-801 or amphetamine pretreated animals, statistical comparisons were made for the MK-801 or d-amphetamine-controls, respectively.

ED ₅₀ values for the reduction of amphetamine-induced hyper-motion are calculated by curve fitting. For most compounds, the assessment is based on 16 amphetamine pretreated animals over dose range 0, 11, 33 and 100 μmol / kg (subcutaneous) in one single experiment, with supplemental doses in separate experiments. The calculation is based on the distance for the last 45 minutes of the 1 hour measurement. This distance is normalized to the amphetamine-control and fitted by least square minimization to the function “final value- (final value-control) / (1+ (dose / ED ₅₀ ) ^slope )”. Four parameters (control, final value, ED ₅₀ and slope) are fitted to conditions: ED ₅₀ > 0, 0.5 <slope <3, final value = control 0%. Conditions with closed final values focus on potential rather than efficacy. To estimate the confidence level for this parameter, the fitting is repeated 100 times with random uniformly distributed square weights (0 to 1) for each measurement. The ED ₅₀ -ranges presented include 95% of these values.

In vivo testing: neurochemistry

After a behaviorally active session, rats are beheaded and their brains quickly collected and placed on an ice cold petri-plate. The limbic systemic forebrain, striatum, frontal cortex and remaining hemisphere sections of each rat were excised and frozen. Each brain section is analyzed sequentially for the amount of monoamines and their metabolites.

Monoamine transporter materials (NA (noradrenaline), DA (dopamine), 5-HT (serotonin)) as well as their amines (NM (normethaneephrine), 3-MT (3-methoxytyramine)) and acids (DOPAC (3,4-dihydroxyphenylacetic acid), 5-HIAA (5-hydroxyindolacetic acid), HVA (homovanic acid)) metabolites were analyzed in brain tissue homogenate by HPLC separation and electrochemical detection. Quantify

The analytical method is based on two chromatographic separations provided for amines or acids. The two chromatographic separations share a common autoinjector with a 10-port valve and two sample loops for simultaneous injection for two systems. Two systems are equipped with reversed phase columns (Luna C18 (2), dp 3 μm, 50 * 2 mm id, Phenomenex), and electrochemical detection is achieved at two potentials on the glassy carbon electrode (MF-1000, Bioanalytical Systems) , Inc.). The column effluent is passed through the T-junction to the detection cell or waste outlet. This is accomplished by two solenoid valves, which block the waste or detector outlet. By preventing the chromatography front part from reaching the detector, a better detection state is achieved. The aqueous mobile phase of the acid system (0.4 ml / min) contains 14 mM citric acid, 10 mM sodium citrate, 15% MeOH (v / v) and 0.1 mM EDTA. Detection potentials for the Ag / AgCl reference are 0.45 and 0.60V. The aqueous ion pair mobile phase of the amine system (0.5 ml / min) is 5 mM citric acid, 10 mM sodium citrate, 9% MeOH (v / v), MeCN 10.5% (v / v), decane sulfonic acid 0.45 mM and EDTA Contains 0.1 mM. Detection potentials for the Ag / AgCl reference are 0.45 and 0.65V.

ED ₅₀ values for increase of DOPAC in striatum are calculated by curve fitting. For most compounds, the assessment is based on 20 animals spanning dose ranges 0, 3.7, 11, 33 and 100 μmol / kg (subcutaneous) in one single experiment, with supplemental doses in separate experiments. DOPAC levels are normalized to the control and fitted by least square minimization for the function “final value- (final value-control) / (1+ (dose / ED ₅₀ ) ^slope )”. Four parameters (control, final value, ED ₅₀ and slope) are fitted with conditions: ED ₅₀ > 0, 0.5 <slope <3, 350 <final value <400% control. To estimate the confidence level for this parameter, the fitting is repeated 100 times with random uniformly distributed square weights (0 to 1) for each measurement. The ED ₅₀ -ranges presented include 95% of these values.

In Vivo Testing: Oral Bioavailability

Experiments are performed 24 hours after implantation of arterial and venous catheters. Test compounds are administered orally at 12.5 μmol / kg or intravenously at 5 μmol / kg using an intravenous catheter (n = 3 per group). Arterial blood samples are then collected for 6 hours at 0, 3, 9, 27, 60, 120, 180, 240, 300 and 360 minutes after administration of the test compound. Oral bioavailability is calculated as the ratio of AUC obtained after oral administration to AUC obtained after intravenous administration in each rat. The parameter AUC is calculated as follows:

AUC: Clast under the plasma concentration versus time curve from time 0 to the final measured concentration (calculated by log / linear trapezoidal method).

The level of test compound is determined by Liquid Chromatography-Mass Spectrum (LC-MS) (Hewlett-Packard 1100MSD Series). The LC-MS module includes a four-way pump system, vacuum degasser, a thermostatic autosampler, a thermostated column compartment, a diode array detector and an API-ES spray chamber. Data handling is provided by HP ChemStation rev.A.06.03. To the system. Device Settings: MSD Mode: Selected Ion Monitoring (SIM) MSD Polarity: Positive Gas Temperature: 350 ° C. Dry Gas: 13,0 l / min Spray Gas: 50 psig Capillary Voltage: 5000 V Fragmentor Voltage: 70 V

Analytical column: Zorbax Eclipse XDB-C8 (4.6 * 150 mm, 5 μιη) at 20 ° C. Mobile phases are acetic acid (0,03%) (solvent A) and acetonitrile (solvent B). The flow rate of the mobile phase is 0,8 ml / min. Elution begins with isocratic in 12% solvent B for 4,5 minutes and then increases linearly to 60% over 4,5 minutes.

Extraction Process: Plasma samples (0,25-0.5 ml) are diluted to 1 ml with water and 60 pmol (100 μl) internal standard (-)-OSU6241 is added. The pH is adjusted to 11 by addition of 25 μl saturated Na ₂ CO ₃ . After mixing, the sample is shaken for 20 minutes and extracted with 4 ml dichloromethane. The organic layer is transferred to a smaller tube after centrifugation and evaporated to dryness under a nitrogen stream. The residue is then dissolved for LC-MS analysis (10 μl injected) in 120 μl mobile phase (acetic acid (0,03%): acetonitrile, 95: 5). Selective ions (MH ⁺ ) are monitored for each example and MH ⁺ 296 is monitored for (-)-OSU6241 ((3- [3- (ethylsulfonyl) phenyl] -1-propylpiperidine) .

Standard curves ranging from 1 to 500 pmmol are prepared by adding the appropriate amount of test compound to the blank plasma sample.

In vitro test: Metabolic stability in rat liver microsomes

Forlin L: Effects of Clophen A50, 3-methylcholantrene, pregnenolone-16aq-carbonitrile and Phenobarbital on the hepatic microsomal cytochrome P-450-dependent monooxygenaser system in rainbow trout, salmo gairdneri, of different age and sex; Tox. Appl. Pharm. 1980 54 (3) 420-430 and homogenized 3 mL / g liver of 0.1 M Na / K * PO ₄ buffer (pH 7.4) (buffer 1) with 0.15 M KCl, for example. After addition, the homogenate is centrifuged for 20 minutes instead of 15 minutes, the supernatant is ultracentrifuged at 100.000 g instead of 105.000 g, and the pellet from the ultracentrifuge is 20% v / v 87% glycerol in buffer 1 Resuspend in between 1 mL / g.

Dilute 1 μL, 0.2 or 1 mM test material with water, mix 10 μL 20 mg / mL rat liver microsomes with 149 μL 37 ° C. Buffer 1, and add 40 μL 4.1 mg / mL NADPH to initiate the reaction. After incubation for 0 or 15 minutes at 37 ° C. on a heating block (LAB-LINE, MULTI-BLOK Heater or lab4you, TS-100 Thermo shaker at 700 rpm), the reaction is stopped by addition of 100 μl pure acetonitrile. The pellet is then discarded after centrifugation at 10.000g (Heraeus, Biofuge fresco) at 4 ° C. for 10 minutes to remove protein precipitates. Test compounds were Zorbax SB-C18 columns (2.1 * 150 mm, 5 μm) using 0.03% formic acid and acetonitrile as mobile phase (gradient) and Zorbax using 0.03% acetic acid and acetonitrile as mobile phase (gradient) Analyze using HPLC-MS (Hewlett-Packard 1100MSD series) with Eclipse XDB-18 (3 * 75 mm, 3.5 μm). The 15 minute conductance is calculated as the fraction of test compounds removed after 15 minutes, expressed as% at 0 minute levels, ie 100 * [test compound concentration at 0 min-concentration at 15 min] / concentration at 0 min.

The preparation of liver microsomes is described in Forlin L: Effects of Clophen A50, 3-methylcholantrene, pregnenolone-16aq-carbonitrile and Phenobarbital on the hepatic microsomal cytochrome P-450-dependent monooxygenaser system in rainbow trout, salmo gairdneri, of different age and sex; Tox. Appl. Pharm. 1980 54 (3) 420-430.

Protocols for incubation with liver microsomes are described in Crespi & Stresser (Crespi CL, DM Stressser: Fluorometric screening for metabolism based drug-drug interactions; J. Pharm. Tox. Meth. 2000 44 325-331] and Renwick et al. [Renwick et al .: Metabolism of 2,5-bis (trifluoromethyl) -7-benzyloxy-4-trifluoromethylcoumarin by human hepatic CYP isoforms: evidence for selectivity towards CYP3A4; Xenobiotica 2001 31 (4) 187-204.

Microdialysis

Female Sprague Dawley rats weighing 220-320 g are used throughout the experiment. Animals are housed in groups of five animals in each cage prior to testing and free access to water and food. Animals are housed for at least 1 week after arrival prior to use in surgery and experiments. Each rat is used only once for microdialysis.

We describe I-shaped probes according to Santiago & Westerink [Santiago M, Westerink BHC: Characterization of the in vivo release of dopamine as recorded by different types of intracerebral microdialysis probes; Naunyn-Schmiedeberg's Arch. Pharmacol. Modified versions of Waters et al. (Waters N, Lofberg L, Haadsma-Svensson S, Svensson K, Sonesson C and Carlsson A: Differential effects of dopamine D2 and D3) for 1990 342 407-414. receptor antagonists in regard to dopamine release, in vivo receptor displacement and behaviour. "J. Neural. Transm. Gen. Sect. 1994 98 (1) 39-55. The dialysis membrane used by the inventors is AN69 polyacrylonitrile. / Sodium metallylsulfonate copolymer (HOSPAL; od / id 310/220 μm: Gambro, Lund, Sweden) etc. In the striatum, the present inventors have an exposed length of dialysis membrane of 3 mm and a corresponding length in the frontal cortex. A 2.5 mm probe is used Rats are operated under isoflurane inhalation anesthesia and placed on a Kopf stereotactic device with coordinates Paxinos & Watson, Paxinos G, Watson C: Brain in Stereotaxic Coordinates; Academic Press, New York 1986, etc .; junction points; dorsal striatum AP +1, ML ± 2.6, DV -6.3; Pf cortex, AP +3.2, 8 ° ML ± 1.2, DV -4.0 Dialysis probes under perforation instructions And are bonded with phosphatine dental cement.

Rats are individually housed in cages for 48 hours prior to dialysis experiments to allow them to recover from surgery and minimize the risk of drug interactions with anesthetics during the following experiments. During this time, the rats have free access to food and water. On the day of the experiment, the rat is connected to a microperfusion pump via a swiwel and replaced in a cage that can move freely within its detention. Perfusion media include Mogaddam & Bunney (Moghaddam B, Bunney BS: Ionic Composition of Microdialysis Perfusing Solution Alters the Pharmacological Responsiveness and Basal Outflow of Striatal Dopamine; J. Neurochem. 1989 53 652-654; 140, CaCl ₂ ; 1.2, KCl; 3.0, MgCl ₂ ; 1.0 and ascorbic acid; Ringer's solution containing 0.04 (mmol / l). The pump is set at a perfusion rate of 2 μl / min and 40 μl samples are collected every 20 minutes.

Each sample is analyzed by two HPLC systems. Two samples are maintained in a row (4 μl and 20 μl) on an auto injector (CMA 200) with a 10 port valve (Valco C10WE) and each brain dialysate sample is loaded into both loops simultaneously. 20 μL samples were injected with dopamine (DA), noradrenaline (NA), normethanephrine (NM), 3-methoxytyramine (3-MT) and serotonin (5-hydroxytrypamine, 5-HT). Introduced into a column switching system (reverse phase combined with reverse phase ion pairs) for measurement, and 4 μl samples were acidic monoamine metabolite 3,4-di-hydroxyphenylacetic acid (DOPAC), homovanic acid (HVA) and 5 Introduced in reverse phase for chromatography of hydroxyindoleacetic acid (5-HIAA). The current generated by the two EC detectors is converted into digital data and evaluated using Chromleon software (Dionex) on the PC. The method sample conduction time is 4.5 minutes and two parallel specimens are standard analyzed simultaneously in the system.

After the experiment, the rat is separated from the perfusion pump and beheaded. Their brains are collected quickly and fixed in Neo-fix solution (Kebo-lab, Sweden) for subsequent probe localization tests. The Animal Ethics Committee in Goteborg, Sweden approved the process applied to these experiments.

Claims (17)

A compound of formula 1, any of its stereoisomers, or all mixtures of stereoisomers thereof, or N-oxides or pharmaceutically acceptable salts thereof:
Formula 1

In Chemical Formula 1,
X is O, S, NH or CH ₂ ;
R ¹ is selected from the group consisting of SOR ⁸ , SO ₂ R ⁸ , SO ₂ NH ₂ , SO ₂ NHCH ₃ and SO ₂ N (CH ₃ );
R ² is selected from the group consisting of H, CN, F, Cl, Br, I and CH ₃ ;
R ³ is C ₁ -C ₅ alkyl, allyl, CH ₂ CH ₂ OCH ₃ , CH ₂ CH ₂ CH ₂ F, CH ₂ CH ₂ CHF ₂ , CH ₂ CH ₂ F, 3,3,3-trifluoropropyl , 4,4,4-trifluorobutyl, CH ₂ CH ₂ OH, CH ₂ CH ₂ CH ₂ OH, CH ₂ CH (OH) CH ₃ , CH ₂ CH ₂ COCH ₃ , C ₃ -C ₆ cycloalkyl,

And

Is selected from the group consisting of;
R ⁴ is H, C ₁ -C ₅ alkyl, allyl, CH ₂ CH ₂ OCH ₃ , CH ₂ CH ₂ CH ₂ F, CH ₂ CH ₂ CHF ₂ , CH ₂ CH ₂ F, 3,3,3-trifluoro Ropropyl, 4,4,4-trifluorobutyl, CH ₂ CH ₂ OH, CH ₂ CH ₂ CH ₂ OH, CH ₂ CH (OH) CH ₃ , CH ₂ CH ₂ COCH ₃ ,

And

Selected from the group consisting of;
R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 4 to 6 membered heterocyclic ring, wherein the heterocyclic ring is one oxygen atom and / or one additional nitrogen atom as ring member May optionally include; The heterocyclic ring may be optionally substituted with C ₁ -C ₅ alkyl;
R ⁵ , R ⁶ and R ⁷ are selected from the group consisting of H and CH ₃ ;
R ⁸ is selected from the group consisting of C ₁ -C ₃ alkyl, CF ₃ , CHF ₂ , CH ₂ F and CN. The compound of formula 1, any of its stereoisomers, or any mixture of stereoisomers thereof, or N-oxides or pharmaceutically acceptable thereof according to claim 1, wherein X is O, S, NH or CH ₂ . Salts thereof. The method according to claim 1 or 2,
R ¹ is selected from the group consisting of SOR ⁸ , SO ₂ R ⁸ , SO ₂ NH ₂ , SO ₂ NHCH ₃ and SO ₂ N (CH ₃ );
A compound of Formula 1, any of its stereoisomers, or any mixture of stereoisomers thereof, wherein R ⁸ is selected from the group consisting of C ₁ -C ₃ alkyl, CF ₃ , CHF ₂ , CH ₂ F and CN, or Their N-oxides or pharmaceutically acceptable salts thereof. 4. The method according to any one of claims 1 to 3,
R ¹ is selected from the group consisting of H, CN, F, Cl, Br, I and CH ₃ , a compound of Formula 1, any of its stereoisomers, or any mixture of stereoisomers thereof, or N- Oxides or pharmaceutically acceptable salts thereof. 5. The method according to any one of claims 1 to 4,
R ³ is C ₁ -C ₅ alkyl, allyl, CH ₂ CH ₂ OCH ₃ , CH ₂ CH ₂ CH ₂ F, CH ₂ CH ₂ CHF ₂ , CH ₂ CH ₂ F, 3,3,3-trifluoropropyl , 4,4,4-trifluorobutyl, CH ₂ CH ₂ OH, CH ₂ CH ₂ CH ₂ OH, CH ₂ CH (OH) CH ₃ , CH ₂ CH ₂ COCH ₃ , C ₃ -C ₆ cycloalkyl,

And

A compound of Formula 1, any of its stereoisomers, or all mixtures of stereoisomers thereof, or N-oxides or pharmaceutically acceptable salts thereof, selected from the group consisting of: The method according to any one of claims 1 to 5,
R ⁴ is H, C ₁ -C ₅ alkyl, allyl, CH ₂ CH ₂ OCH ₃ , CH ₂ CH ₂ CH ₂ F, CH ₂ CH ₂ CHF ₂ , CH ₂ CH ₂ F, 3,3,3-trifluoro Ropropyl, 4,4,4-trifluorobutyl, CH ₂ CH ₂ OH, CH ₂ CH ₂ CH ₂ OH, CH ₂ CH (OH) CH ₃ , CH ₂ CH ₂ COCH ₃ ,

And A compound of Formula 1, any of its stereoisomers, or all mixtures of stereoisomers thereof, or N-oxides or pharmaceutically acceptable salts thereof, selected from the group consisting of: The method according to any one of claims 1 to 5,
R ³ and R ⁴ , together with the nitrogen atom to which they are attached, form a 4-6 membered heterocyclic ring, wherein the heterocyclic ring represents one oxygen atom and / or one additional nitrogen atom as ring member. Optionally includes; The heterocyclic ring may be optionally substituted with C ₁ -C ₅ alkyl, a compound of Formula 1, any of its stereoisomers, or any mixture of stereoisomers thereof, or N-oxides or pharmaceutically acceptable thereof Salts thereof. The method according to any one of claims 1 to 7,
A compound of Formula 1, any of its stereoisomers, or any mixture of stereoisomers thereof, or N-oxides or pharmaceuticals thereof, wherein R ⁵ , R ⁶ and R ⁷ are selected from the group consisting of H and CH ₃ Acceptable salts thereof. The method of claim 1,
X is O or CH ₂ ;
R ¹ is SO ₂ R ⁸ ;
R ² is H, F or Cl;
R ³ is C ₁ -C ₅ alkyl, allyl, CH ₂ CH ₂ OCH ₃ , 3,3,3-trifluoropropyl or CH ₂ CH ₂ OH;
R ⁴ is H or C ₁ -C ₅ alkyl;
R ³ and R ⁴ together with the nitrogen atom to which they are attached form an acetidine, pyrrolidine, piperidine, C ₁ -C ₅ alkyl-piperidine or morpholine group;
R ⁵ , R ⁶ and R ⁷ are all H;
A compound of Formula 1, any of its stereoisomers, or any mixture of stereoisomers thereof, or N-oxides or pharmaceutically acceptable salts thereof, wherein R ⁸ is C ₁ -C ₃ alkyl or CF ₃ . The method of claim 1,
N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -propan-1-amine;
N-{[(2R) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -propan-1-amine;
N-{[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -propan-1-amine;
N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;
N-{[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;
1-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} piperidine;
1-{[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} piperidine;
1-{[(2R) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} piperidine;
N-methyl-1- [7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxyn-2-yl] methanamine;
N-methyl-1-[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxyn-2-yl] methanamine;
1-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} pyrrolidine;
3-methyl-1-{[(2R) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} piperidine;
2-methyl-N-{[(2R) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine;
2-methyl-N-{[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine;
N-methyl-N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine;
N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-propylpropan-1-amine;
N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-propan-1-amine;
N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;
N-{[(2S) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;
1- [5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] -N-methylmethanamine;
N-{[(2S) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine;
N-{[(2S) -7- (trifluoromethylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;
N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} -N-propan-1-amine;
N-{[(2S) -7- (trifluoromethylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine;
N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} prop-2-en-1-amine;
4-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} morpholine;
N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} butan-1-amine;
N, N-dimethyl-N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methanamine;
N-ethyl-N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;
N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-2-amine;
N-ethyl-N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-propan-1-amine;
2-({[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} amino) ethanol;
N-methyl-N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;
2-methoxy-N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;
1-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} azetidine;
2-methyl-N-{[7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine;
N-{[(2S) -8-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;
N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;
N-{[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N- (3,3,3-trifluoro Propyl) amine;
N-{[(2S) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N- (3,3, 3-trifluoropropyl) amine;
1-[(2S) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] -N-methylmethanamine;
N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} prop-2-en-1-amine;
4-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} morpholine;
N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} butan-1-amine;
N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-propylpropan-1-amine;
1- [5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] -N, N-dimethylmethanamine;
N-ethyl-N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;
N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-2-amine;
N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-methylpropan-1-amine;
N-ethyl-N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine;
2-({[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} amino) ethanol;
N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-methylethanamine;
N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -2-methoxyethanamine;
1-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} azetidine;
N-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -2-methylpropan-1-amine;
1-{[5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} pyrrolidine;
N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} prop-2-ene-1- Amines;
N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} butan-1-amine;
N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-propylpropan-1-amine ;
1-[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] -N, N-dimethylmethanamine;
N-ethyl-N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} ethanamine;
N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-2-amine;
N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-methylpropan-1-amine ;
N-ethyl-N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine ;
2-({[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} amino) ethanol;
N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -N-methylethanamine;
N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -2-methoxyethanamine;
1-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} azetidine;
N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -2-methylpropan-1-amine ;
1-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} pyrrolidine;
N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -propan-1-amine;
N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -3-fluoropropane-1- Amines;
N-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -2,2-dimethylpropane-1 Amines;
1-{[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} piperidine;
1-[(2S) -5-chloro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] -N-methylmethanamine;
N-{[(2S) -5-fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} -propan-1-amine;
2,2-dimethyl-N-{[(2S) -7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} propan-1-amine;
N-methyl-1- [7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methanamine;
N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} ethanamine;
N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} prop-2-en-1-amine;
4-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} morpholine;
N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} butan-1-amine;
N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} -N-propylpropan-1-amine;
N, N-dimethyl-1- [7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methanamine;
N-ethyl-N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} ethanamine;
N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} propan-2-amine;
N-methyl-N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} propan-1-amine;
N-ethyl-N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} propan-1-amine;
2-({[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} amino) ethanol;
N-methyl-N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} ethanamine;
2-methoxy-N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} ethanamine;
1-{[7- (methylsulfonyl) -3,4-dihydro-2H-croken-2-yl] methyl} azetidine;
2-methyl-N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} propan-1-amine;
1-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} pyrrolidine;
1-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} piperidine;
3-fluoro-N-{[7- (methylsulfonyl) -3,4-dihydro-2H-chromen-2-yl] methyl} propan-1-amine;
4-{[(S) -5-Fluoro-7- (methylsulfonyl) -2,3-dihydro-1,4-benzodioxin-2-yl] methyl} morpholine; or
N-({(2S) -7-[(trifluoromethyl) sulfonyl] -2,3-dihydro-1,4-benzodioxin-2-yl} methyl) propan-2-amine A compound of 1, any of its stereoisomers, or all mixtures of stereoisomers thereof, or N-oxides or pharmaceutically acceptable salts thereof. A compound according to any one of claims 1 to 10, any of its stereoisomers, or any mixture of stereoisomers thereof, or N, together with one or more pharmaceutically acceptable carriers, excipients or diluents A pharmaceutical composition comprising a therapeutically effective amount of an oxide or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 10, for use as a medicament, a compound, any of stereoisomers thereof, or any mixture of stereoisomers thereof, or N-oxides or pharmaceutically acceptable thereof. Salts thereof. The compound of any one of claims 1 to 10 for use in the treatment, prevention or alleviation of a disease, disorder or condition in response to the modulation of dopaminergic function in the central nervous system of a mammal, including a human, Any of its stereoisomers, or all mixtures of stereoisomers thereof, or N-oxides or pharmaceutically acceptable salts thereof. A compound according to any one of claims 1 to 10, any of its stereoisomers, or any mixture of stereoisomers thereof, or N-oxides or pharmaceutically acceptable thereof, for the preparation of a medicament Use of salts. Use according to claim 14 for the preparation of a pharmaceutical composition for the treatment, prevention or alleviation of a disease, disorder or condition in mammals including humans in response to modulation of dopaminergic function in the central nervous system. The method of claim 15, wherein the disease, disorder or condition is dyskinesia, Parkinson's disease, Parkinson's syndrome, dyskinesia, L-DOPA induced dyskinesia, dysfunction, tics, tremor, Huntington's disease, spitiness Psychosis and hallucinations, non-human psychosis and hallucinations, schizophrenia, schizophrenic disorders, bipolar disorders, mood disorders, anxiety disorders, depression, OCD, neurodevelopmental disorders, autism categorical disorders, ADHD, cerebral palsy, Gilles de la Tourette's syndrome, degenerative neuropathy, dementia, senile cognitive impairment, sleep disorders, sexual disorders, eating disorders, obesity, headache, pain in conditions characterized by increased muscle tension, drugs Use for people with dementia associated with abuse, Alzheimer's disease or Alzheimer's disease. A therapeutically effective amount of a compound according to any one of claims 1 to 10, any of its stereoisomers, or all mixtures of stereoisomers thereof, or N-oxides or pharmaceutically acceptable salts thereof thereof. Administering to the body of a living animal in need of treatment, prevention or alleviation of a disease, disorder or condition in response to control of dopaminergic function in the central nervous system. A method of treating, preventing or alleviating a disease, disorder or condition in response to modulation of dopaminergic function.